Thiazole Compound and Use Thereof

ABSTRACT

An object of the present invention is to provide a novel thiazole compound with specific inhibitory activity against phosphodiesterase 4. 
 
The present invention provides a compound represented by Formula (1), an optical isomer thereof, or a salt thereof:  
                 
 
wherein R1 is a di-C 1-6  alkoxyphenyl group; R2 is any one of the following groups (a) to (t): (a) a phenyl group; (b) a naphthyl group; (c) a pyridyl group; (d) a furyl group; (e) a thienyl group; (f) an isoxazolyl group; (g) a thiazolyl group; (h) a pyrrolyl group; (i) an imidazolyl group; (j) a tetrazolyl group; (k) a pyrazinyl group; (l) a thienothienyl group; (m) a benzothienyl group; (n) an indolyl group; (o) a benzimidazolyl group; (p) an indazolyl group; (q) a quinolyl group; (r) a 1,2,3,4-tetrahydroquinolyl group; (s) a quinoxalinyl group; and (t) a 1,3-benzodioxolyl group; and A is any one of the following groups (i) to (vi): (i) —CO—B— wherein B is a C 1-6  alkylene group; (ii) —CO—Ba wherein Ba is a C 2-6  alkenylene group; (iii) —CH(OH)—B—; (iv) —COCH(COOR3)-Bb- wherein R3 is a C 1-6  alkyl group and Bb is a C 1-6  alkylene group; and (v) -Bc- wherein Bc is a C 2-6  alkylene group.

TECHNICAL FIELD

The present invention relates to a novel thiazole compound. The presentinvention further relates to a pharmaceutical composition comprising thethiazole compound.

BACKGROUND ART

Researchers have recently discovered that cyclic adenosine3′,5′-monophosphate (cAMP), which acts as an intracellular secondmessenger, controls the activity of inflammatory cells, such aslymphocytes, neutrophiles, eosinophiles, mast cells, etc. It is knownthat cAMP is degraded to 5′-AMP, which does not act as a messenger, bythe action of phosphodiesterase (PDE), and that PDE adjusts theintracellular cAMP concentration. Since PDE has such a closerelationship with the intracellular cAMP concentration, controlling PDEactivity is believed to be effective against diseases for whichtherapeutic effects are expected to be exhibited by controlling theincrease or decrease of the cAMP concentration (Non-Patent Documents 1and 2).

Eleven types of PDE isozymes (PDEs 1 to 11) are known, and their in vivodistributions are known to vary among different tissues (Non-PatentDocuments 3 and 4). Reportedly, inhibitors specific to PDE4 suppress thefunctions of inflammatory cells, and are believed to be useful againstconjunctivitis, asthma and like inflammatory allergic diseases, andmultiple sclerosis, articular rheumatism and like autoimmune diseases(Non-Patent Documents 5 to 14).

Theophylline has been hitherto used as a PDE inhibitor for treatingasthma. However, theophylline is known to nonspecifically inhibitvarious PDE isozymes, and thus inhibits not only PDE4 but also PDE3 andother isozymes. The inhibition of PDE3 is suspected of causingcardiotonic action and/or central action and producing positiveinotropic and chronotropic effects in the heart (Patent Document 15).Therefore, the use of theophylline as a PDE inhibitor poses the problemof side effects.

Some compounds with specific inhibitory activity against PDE 4 have beenreported (Patent Documents 1 and 2). However, such PDE4 inhibitors haveproblems in that they bind to the high affinity rolipram binding site(HARBS) in the central nervous system and the alimentary canal andproduce side effects, such as emesis induction and nausea, or havedrawbacks in that they show insufficient PDE4 inhibitory activity. Thus,heretofore known PDE4 inhibitors have not been used clinically astherapeutic agents.

In view of this prior art, the development of a compound thateffectively exhibits, without side effects, specific inhibitory activityagainst PDE4 is desired.

-   [Patent Document 1] Japanese Unexamined Patent Publication No.    1975-157360-   [Patent Document 2] Japanese Unexamined Patent Publication No.    2003-64057-   [Non-Patent Document 1] Trends Pharmacol. Sci. 18: 164-170, 1997-   [Non-Patent Document 2] Immunopharmacology 47: 127-162, 2000-   [Non-Patent Document 3] J. Allergy. Clin. Immunol. 108: 671-680,    2001-   [Non-Patent Document 4] Mol. Pharmacol. 64: 533-546, 2003-   [Non-Patent Document 5] Am. J. Respir. Crit. Care. Med. 157:    351-370, 1998-   [Non-Patent Document 6] Monaldi. Arch. Chest. Dis. 57: 48-64, 2002-   [Non-Patent Document 7] Arzneimittelforschung 44: 163-165, 1994-   [Non-Patent Document 8] Eur. J. Pharmacol. 229: 45-53, 1992-   [Non-Patent Document 9] Inflammation 17: 25-31, 1993-   [Non-Patent Document 10] Nat. Med. 1: 244-248, 1995-   [Non-Patent Document 11] J. Neuroimmunol. 79: 54-61, 1997-   [Non-Patent Document 12] Clin. Exp. Immunol. 100: 126-132, 1995-   [Non-Patent Document 13] Clin. Exp. Immunol. 108: 415-419, 1997-   [Non-Patent Document 14] J. Immuno. 159: 6253-6259, 1997-   [Non-Patent Document 15] Physiol. Rev. 76: 725-748, 1995-   [Non-Patent Document 16] J. Clin. Pathol. 54: 577-589, 2001-   [Non-Patent Document 17] Curr. Drug Targets Inflamm. Allergy 1:    377-392, 2002-   [Non-Patent Document 18] Curr. Opin. Pharmacol. 3: 449-455, 2003-   [Non-Patent Document 19] J. Infus. Nurs. 26: 319-325, 2003

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to solve the above problems of theprior art. Specifically, an object of the present invention is toprovide a novel thiazole compound that has specific inhibitory activityagainst PDE4, and a pharmaceutical composition comprising the compound.Another object of the present invention is to provide a PDE4 inhibitorthat exhibits specific inhibitory activity against PDE4. A furtherobject of the present invention is to provide a preventive ortherapeutic agent for atopic dermatitis, and a method for treatingatopic dermatitis.

Means for Solving the Problems

The present inventors searched for a new compound that has PDE4inhibitory activity, and found that a thiazole compound with a newstructure has strong PDE4 inhibitory activity that is highly specificand dissociated from HARBS binding activity. The inventors further foundthat the thiazole compound exhibits preventive or therapeutic effectsagainst atopic dermatitis because of its PDE4 inhibitory activity.

The inventors further found that the thiazole compound also exhibitsTNF-α production inhibitory activity and IL-4 production inhibitoryactivity. In chronic inflammatory diseases, such as autoimmune diseasesand allergic diseases, cytokines produced by immunocompetent cells areknown as important inflammatogenic mediators. Among such cytokines,tumor necrosis factor (TNF)-α and interleukin (IL)-4 are believed toplay important roles (Non-Patent Documents 16 to 19). Accordingly,compounds with TNF-α production inhibitory activity or IL-4 productioninhibitory activity are clinically useful.

The present invention was accomplished by conducting further researchbased on the above findings.

The present invention provides the following thiazole compounds.

1. A compound represented by Formula (1), an optical isomer thereof, ora salt thereof:

wherein R1 is a di-C₁₋₆ alkoxyphenyl group;

R2 is any one of the following groups (a) to (t):

(a) a phenyl group in which the phenyl ring may be substituted with oneor more members selected from the group consisting of (a-1) hydroxygroups, (a-2) halogen atoms, (a-3) unsubstituted or halogen-substitutedC₁₋₆ alkyl groups, (a-4) unsubstituted or halogen-substituted C₁₋₆alkoxy groups, (a-5) C₁₋₆ alkoxy-C₁₋₆ alkoxy groups, (a-6) amino-C₁₋₆alkoxy groups which may be substituted with a C₁₋₆ alkyl group orgroups, (a-7) methylenedioxy groups, (a-8) carboxyl groups, (a-9)phenoxy groups, (a-10) C₁₋₆ alkoxycarbonyl groups, (a-11) C₁₋₆alkanoyloxy groups, (a-12) C₁₋₆ alkanoyl groups, (a-13) cyano groups,(a-14) nitro groups, (a-15) C₁₋₆ alkylcarbamoyl groups, (a-16)aminosulfonyl groups, (a-17) amino groups which may be substituted witha C₁₋₆ alkyl group or groups, (a-18) C₁₋₆ alkanoylamino groups, (a-19)C₁₋₆ alkylthio groups, (a-20) phenyl groups, (a-21) pyrazolyl groups,(a-22) imidazolyl groups, (a-23) triazolyl groups, (a-24) morpholinogroups, (a-25) pyrrolidinyl groups, (a-26) piperazinylcarbonyl groupswhich may be substituted with a C₁₋₆ alkyl group or groups, and (a-27)phenyl-C₁₋₆ alkoxy groups;

(b) a naphthyl group;

(c) a pyridyl group in which the pyridine ring may be substituted withone or more members selected from the group consisting of (c-1) hydroxygroups, (c-2) C₁₋₆ alkyl groups, (c-3) C₁₋₆ alkoxy groups, (c-4)phenyl-C₁₋₆ alkoxy groups, and (c-5) C₁₋₆ alkoxycarbonyl groups;

(d) a furyl group in which the furan ring may be substituted with a C₁₋₆alkyl group or groups;

(e) a thienyl group in which the thiophene ring may be substituted withone or more members selected from the group consisting of (e-1) halogenatoms, (e-2) C₁₋₆ alkyl groups, and (e-3) C₁₋₆ alkoxy groups;

(f) an isoxazolyl group in which the isoxazolyl ring may be substitutedwith a C₁₋₆ alkyl group or groups;

(g) a thiazolyl group in which the thiazole ring may be substituted withone or more members selected from the group consisting of (g-1) C₁₋₆alkyl groups, and (g-2) phenyl groups which may be substituted with aC₁₋₆ alkoxy group or groups;

(h) a pyrrolyl group in which the pyrrole ring may be substituted with aC₁₋₆ alkyl group or groups;

(i) an imidazolyl group in which the imidazole ring may be substitutedwith a C₁₋₆ alkyl group or groups;

(j) a tetrazolyl group;

(k) a pyrazinyl group;

(l) a thienothienyl group;

(m) a benzothienyl group;

(n) an indolyl group in which the indole ring may be substituted with aC₁₋₆ alkoxy group or groups;

(o) a benzimidazolyl group in which the benzimidazole ring may besubstituted with a C₁₋₆ alkyl group or groups;

(p) an indazolyl group;

(q) a quinolyl group;

(r) a 1,2,3,4-tetrahydroquinolyl group in which the1,2,3,4-tetrahydroquinoline ring may be substituted with an oxo group orgroups;

(s) a quinoxalinyl group; and

(t) a 1,3-benzodioxolyl group; and

A is any one of the following groups (i) to (vi):

(i) —CO—B— wherein B is a C₁₋₆ alkylene group;

(ii) —CO—Ba— wherein Ba is a C₂₋₆ alkenylene group;

(iii) —CH(OH)—B— wherein B is as defined above;

(iv) —COCH(COOR3)-Bb- wherein R3 is a C₁₋₆ alkyl group and Bb is a C₁₋₆alkylene group; and

(v) -Bc- wherein Bc is a C₂₋₆ alkylene group.

2. A compound according to Item 1, wherein, in Formula (1), R1 is a3,4-di-C₁₋₆ alkoxyphenyl group; an optical isomer thereof; or a saltthereof.

3. A compound according to Item 1, wherein, in Formula (1), R1 is a3,4-dimethoxyphenyl group or a 3,4-diethoxyphenyl group; an opticalisomer thereof; or a salt thereof.

4. A compound according to any one of Items 1 to 3, wherein, in Formula(1), R2 is (a) a phenyl group in which the phenyl ring may besubstituted with one or more members selected from the group consistingof (a-1) hydroxy groups, (a-2) halogen atoms, (a-3) unsubstituted orhalogen-substituted C₁₋₆ alkyl groups, (a-4) unsubstituted orhalogen-substituted C₁₋₆ alkoxy groups, (a-5) C₁₋₆ alkoxy-C₁₋₆ alkoxygroups, (a-6) amino-C₁₋₆ alkoxy groups which may be substituted with aC₁₋₆ alkyl group or groups, (a-7) methylenedioxy groups, (a-8) carboxylgroups, (a-9) phenoxy groups, (a-10) C₁₋₆ alkoxycarbonyl groups, (a-11)C₁₋₆ alkanoyloxy groups, (a-12) C₁₋₆ alkanoyl groups, (a-13) cyanogroups, (a-14) nitro groups, (a-15) C₁₋₆ alkylcarbamoyl groups, (a-16)aminosulfonyl groups, (a-17) amino groups which may be substituted witha C₁₋₆ alkyl group or groups, (a-18) C₁₋₆ alkanoylamino groups, (a-19)C₁₋₆ alkylthio groups, (a-20) phenyl groups, (a-21) pyrazolyl groups,(a-22) imidazolyl groups, (a-23) triazolyl groups, (a-24) morpholinogroups, (a-25) pyrrolidinyl groups, (a-26) piperazinylcarbonyl groupswhich may be substituted with a C₁₋₆ alkyl group or groups, and (a-27)phenyl-C₁₋₆ alkoxy groups;

(c) a pyridyl group in which the pyridine ring may be substituted withone or more members selected from the group consisting of (c-1) hydroxygroups, (c-2) C₁₋₆ alkyl groups, (c-3) C₁₋₆ alkoxy groups, (c-4)phenyl-C₁₋₆ alkoxy groups, and (c-5) C₁₋₆ alkoxycarbonyl groups;

(d) a furyl group in which the furan ring may be substituted with a C₁₋₆alkyl group or groups;

(e) a thienyl group in which the thiophene ring may be substituted withone or more members selected from the group consisting of (e-1) halogenatoms, (e-2) C₁₋₆ alkyl groups, and (e-3) C₁₋₆ alkoxy groups;

(g) a thiazolyl group in which the thiazole ring may be substituted withone or more members selected from the group consisting of (g-1) C₁₋₆alkyl groups, and (g-2) phenyl groups which may be substituted with aC₁₋₆ alkoxy group or groups;

(h) a pyrrolyl group in which the pyrrole ring may be substituted with aC₁₋₆ alkyl group or groups; or

(i) an imidazolyl group in which the imidazole ring may be substitutedwith a C₁₋₆ alkyl group or groups; an optical isomer thereof; or a saltthereof.

5. A compound according to any one of Items 1 to 3, wherein, in Formula(1), R2 is (a) a phenyl group in which the phenyl ring may besubstituted with one or more members selected from the group consistingof (a-1) hydroxy groups, (a-2) halogen atoms, (a-3) unsubstituted orhalogen-substituted C₁₋₆ alkyl groups, (a-4) unsubstituted orhalogen-substituted C₁₋₆ alkoxy groups, (a-5) C₁₋₆ alkoxy-C₁₋₆ alkoxygroups, (a-6) amino-C₁₋₆ alkoxy groups which may be substituted with aC₁₋₆ alkyl group or groups, (a-7) methylenedioxy groups, (a-8) carboxylgroups, (a-9) phenoxy groups, (a-10) C₁₋₆ alkoxycarbonyl groups, (a-11)C₁₋₆ alkanoyloxy groups, (a-12) C₁₋₆ alkanoyl groups, (a-13) cyanogroups, (a-14) nitro groups, (a-15) C₁₋₆ alkylcarbamoyl groups, (a-16)aminosulfonyl groups, (a-17) amino groups which may be substituted witha C₁₋₆ alkyl group or groups, (a-18) C₁₋₆ alkanoylamino groups, (a-19)C₁₋₆ alkylthio groups, (a-20) phenyl groups, (a-21) pyrazolyl groups,(a-22) imidazolyl groups, (a-23) triazolyl groups, (a-24) morpholinogroups, (a-25) pyrrolidinyl groups, (a-26) piperazinylcarbonyl groupswhich may be substituted with a C₁₋₆ alkyl group or groups, and (a-27)phenyl-C₁₋₆ alkoxy groups;

(c) a pyridyl group in which the pyridine ring may be substituted withone or more members selected from the group consisting of (c-1) hydroxygroups, (c-2) C₁₋₆ alkyl groups, (c-3) C₁₋₆ alkoxy groups, (c-4)phenyl-C₁₋₆ alkoxy groups, and (c-5) C₁₋₆ alkoxycarbonyl groups; or

(g) a thiazolyl group in which the thiazole ring may be substituted withone or more members selected from the group consisting of (g-1) C₁₋₆alkyl groups, and (g-2) phenyl groups which may be substituted with aC₁₋₆ alkoxy group or groups; an optical isomer thereof; or a saltthereof.

6. A compound according to any one of Items 1 to 5, wherein, in Formula(1), A is (i) —CO—B— wherein B is a methylene group, an ethylene groupor a trimethylene group; (ii) —CO—Ba— wherein Ba is a vinylidene group;(iii) —CH(OH)—B— wherein B is a methylene group or an ethylene group;(iv) —COCH(COOR3)-Bb- wherein R3 is a methyl group, an ethyl group or atert-butyl group and Bb is a methylene group or an ethylene group; or

(v) -Bc- wherein Bc is an ethylene group, a trimethylene group or atetramethylene group; an optical isomer thereof; or a salt thereof.

7. A compound according to any one of Items 1 to 5, wherein, in Formula(1), A is (i) —CO—B— wherein B is an ethylene group; (iii) —CH(OH)—B—wherein B is an ethylene group;

(iv) —COCH(COOR3)-Bb- wherein R3 is a methyl group and Bb is a methylenegroup; or (v) -Bc- wherein Bc is a trimethylene group; an optical isomerthereof; or a salt thereof.

8. A compound according to Item 1, wherein, in Formula (1), R1 is a3,4-di-C₁₋₆ alkoxyphenyl group;

R2 is (a) a phenyl group in which the phenyl ring may be substitutedwith one or more members selected from the group consisting of (a-1)hydroxy groups, (a-2) halogen atoms, (a-3) unsubstituted orhalogen-substituted C₁₋₆ alkyl groups, (a-4) unsubstituted orhalogen-substituted C₁₋₆ alkoxy groups, (a-5) C₁₋₆ alkoxy-C₁₋₆ alkoxygroups, (a-6) amino-C₁₋₆ alkoxy groups which may be substituted with aC₁₋₆ alkyl group or groups, (a-7) methylenedioxy groups, (a-8) carboxylgroups, (a-9) phenoxy groups, (a-10) C₁₋₆ alkoxycarbonyl groups, (a-11)C₁₋₆ alkanoyloxy groups, (a-12) C₁₋₆ alkanoyl groups, (a-13) cyanogroups, (a-14) nitro groups, (a-15) C₁₋₆ alkylcarbamoyl groups, (a-16)aminosulfonyl groups, (a-17) amino groups which may be substituted witha C₁₋₆ alkyl group or groups, (a-18) C₁₋₆ alkanoylamino groups, (a-19)C₁₋₆ alkylthio groups, (a-20) phenyl groups, (a-21) pyrazolyl groups,(a-22) imidazolyl groups, (a-23) triazolyl groups, (a-24) morpholinogroups, (a-25) pyrrolidinyl groups, (a-26) piperazinylcarbonyl groupswhich may be substituted with a C₁₋₆ alkyl group or groups, and (a-27)phenyl-C₁₋₆ alkoxy groups;

(c) a pyridyl group in which the pyridine ring may be substituted withone or more members selected from the group consisting of (c-1) hydroxygroups, (c-2) C₁₋₆ alkyl groups, (c-3) C₁₋₆ alkoxy groups, (c-4)phenyl-C₁₋₆ alkoxy groups, and (c-5) C₁₋₆ alkoxycarbonyl groups;

(d) a furyl group in which the furan ring may be substituted with a C₁₋₆alkyl group or groups;

(e) a thienyl group in which the thiophene ring may be substituted withone or more members selected from the group consisting of (e-1) halogenatoms, (e-2) C₁₋₆ alkyl groups, and (e-3) C₁₋₆ alkoxy groups;

(g) a thiazolyl group in which the thiazole ring may be substituted withone or more members selected from the group consisting of (g-1) C₁₋₆alkyl groups, and (g-2) phenyl groups which may be substituted with aC₁₋₆ alkoxy group or groups;

(h) a pyrrolyl group in which the pyrrole ring may be substituted withone or more C₁₋₆ alkyl groups;

(i) an imidazolyl group in which the imidazole ring may be substitutedwith a C₁₋₆ alkyl group or groups; and

A is (i) —CO—B— wherein B is as defined above;

(ii) —CO—Ba wherein Ba is as defined above; (iii) —CH(OH)—B— wherein Bis as defined above; (iv) —COCH(COOR3)-Bb- wherein R3 and Bb are asdefined above; or (v) -Bc- wherein Bc is as defined above; an opticalisomer thereof; or a salt thereof.

9. A compound according to Item 1, wherein, in Formula (1), R1 is a3,4-di-C₁₋₆ alkoxyphenyl group;

R2 is (a) a phenyl group in which the phenyl ring may be substitutedwith one or more members selected from the group consisting of (a-1)hydroxy groups, (a-2) halogen atoms, (a-3) unsubstituted orhalogen-substituted C₁₋₆ alkyl groups, (a-4) unsubstituted orhalogen-substituted C₁₋₆ alkoxy groups, (a-5) C₁₋₆ alkoxy-C₁₋₆ alkoxygroups, (a-6) amino-C₁₋₆ alkoxy groups which may be substituted with aC₁₋₆ alkyl group or groups, (a-7) methylenedioxy groups, (a-8) carboxylgroups, (a-9) phenoxy groups, (a-10) C₁₋₆ alkoxycarbonyl groups, (a-11)C₁₋₆ alkanoyloxy groups, (a-12) C₁₋₆ alkanoyl groups, (a-13) cyanogroups, (a-14) nitro groups, (a-15) C₁₋₆ alkylcarbamoyl groups, (a-16)aminosulfonyl groups, (a-17) amino groups which may be substituted witha C₁₋₆ alkyl group or groups, (a-18) C₁₋₆ alkanoylamino groups, (a-19)C₁₋₆ alkylthio groups, (a-20) phenyl groups, (a-21) pyrazolyl groups,(a-22) imidazolyl groups, (a-23) triazolyl groups, (a-24) morpholinogroups, (a-25) pyrrolidinyl groups, (a-26) piperazinylcarbonyl groupswhich may be substituted with a C₁₋₆ alkyl group or groups, and (a-27)phenyl-C₁₋₆ alkoxy groups;

(c) a pyridyl group in which the pyridine ring may be substituted withone or more members selected from the group consisting of (c-1) hydroxygroups, (c-2) C₁₋₆ alkyl groups, (c-3) C₁₋₆ alkoxy groups, (c-4)phenyl-C₁₋₆ alkoxy groups, and (c-5) C₁₋₆ alkoxycarbonyl groups;

(d) a furyl group in which the furan ring may be substituted with a C₁₋₆alkyl group or groups;

(e) a thienyl group in which the thiophene ring may be substituted withone or more members selected from the group consisting of (e-1) halogenatoms, (e-2) C₁₋₆ alkyl groups, and (e-3) C₁₋₆ alkoxy groups;

(g) a thiazolyl group in which the thiazole ring may be substituted withone or more members selected from the group consisting of (g-1) C₁₋₆alkyl groups, and (g-2) phenyl groups which may be substituted with aC₁₋₆ alkoxy group or groups;

(h) a pyrrolyl group in which the pyrrole ring may be substituted with aC₁₋₆ alkyl group or groups; or

(i) an imidazolyl group in which the imidazole ring may be substitutedwith a C₁₋₆ alkyl group or groups; and

A is (i) —CO—B— wherein B is a methylene group, an ethylene group or atrimethylene group; (ii) —CO—Ba— wherein Ba is a vinylidene group; (iii)—CH(OH)—B— wherein B is a methylene group or an ethylene group; (iv)—COCH(COOR3)-Bb- wherein R3 is a methyl group, an ethyl group or atert-butyl group and Bb is a methylene group or an ethylene group; or(v) -Bc- wherein Bc is an ethylene group, a trimethylene group or atetramethylene group; an optical isomer thereof; or a salt thereof.

10. A compound according to Item 1, wherein, in Formula (1), R1 is a3,4-di-C₁₋₆ alkoxyphenyl group;

R2 is (a) a phenyl group in which the phenyl ring may be substitutedwith one or more members selected from the group consisting of (a-1)hydroxy groups, (a-2) halogen atoms, (a-3) unsubstituted orhalogen-substituted C₁₋₆ alkyl groups, (a-4) unsubstituted orhalogen-substituted C₁₋₆ alkoxy groups, (a-5) C₁₋₆ alkoxy-C₁₋₆ alkoxygroups, (a-6) amino-C₁₋₆ alkoxy groups which may be substituted with aC₁₋₆ alkyl group or groups, (a-7) methylenedioxy groups, (a-8) carboxylgroups, (a-9) phenoxy groups, (a-10) C₁₋₆ alkoxycarbonyl groups, (a-11)C₁₋₆ alkanoyloxy groups, (a-12) C₁₋₆ alkanoyl groups, (a-13) cyanogroups, (a-14) nitro groups, (a-15) C₁₋₆ alkylcarbamoyl groups, (a-16)aminosulfonyl groups, (a-17) amino groups which may be substituted witha C₁₋₆ alkyl group or groups, (a-18) C₁₋₆ alkanoylamino groups, (a-19)C₁₋₆ alkylthio groups, (a-20) phenyl groups, (a-21) pyrazolyl groups,(a-22) imidazolyl groups, (a-23) triazolyl groups, (a-24) morpholinogroups, (a-25) pyrrolidinyl groups, (a-26) piperazinylcarbonyl groupswhich may be substituted with a C₁₋₆ alkyl group or groups, and (a-27)phenyl-C₁₋₆ alkoxy groups;

(c) a pyridyl group in which the pyridine ring may be substituted withone or more members selected from the group consisting of (c-1) hydroxygroups, (c-2) C₁₋₆ alkyl groups, (c-3) C₁₋₆ alkoxy groups, (c-4)phenyl-C₁₋₆ alkoxy groups, and (c-5) C₁₋₆ alkoxycarbonyl groups; or

(g) a thiazolyl group in which the thiazole ring may be substituted withone or more members selected from the group consisting of (g-1) C₁₋₆alkyl groups, and (g-2) phenyl groups which may be substituted with aC₁₋₆ alkoxy group or groups; and

A is (i) —CO—B— wherein B is an ethylene group;

(iii) —CH(OH)—B— wherein B is an ethylene group;

(iv) —COCH(COOR3)-Bb- wherein R3 is a methyl group and Bb is a methylenegroup; or (v) -Bc- wherein Bc is a trimethylene group.

The present invention further provide the following uses of the abovethiazole compounds:

11. A pharmaceutical composition comprising a compound according to anyone of Items 1 to 10, an optical isomer thereof, or a salt thereof.

12. A phosphodiesterase 4 inhibitor comprising as an active ingredient acompound according to any one of Items 1 to 10, an optical isomerthereof, or a salt thereof.

13. An IFN-α production inhibitor comprising as an active ingredient acompound according to any one of Items 1 to 10, an optical isomerthereof, or a salt thereof.

14. An IL-4 production inhibitor comprising as an active ingredient acompound according to any one of Items 1 to 10, an optical isomerthereof, or a salt thereof.

15. A preventive or therapeutic agent for atopic dermatitis, comprisingas an active ingredient a compound according to any one of Items 1 to10, an optical isomer thereof, or a salt thereof.

16. A method for treating atopic dermatitis, comprising the step ofadministering to a human or non-human mammal an effective amount of acompound according to any one of Items 1 to 10, an optical isomerthereof, or a salt thereof.

17. Use of a compound according to any one of Items 1 to 10, an opticalisomer thereof, or a salt thereof, for producing a preventive ortherapeutic agent for atopic dermatitis.

18. Use of a compound according to any one of Items 1 to 10, an opticalisomer thereof, or a salt thereof, for producing a phosphodiesterase 4inhibitor.

19. Use of a compound according to any one of Items 1 to 10, an opticalisomer thereof, or a salt thereof, for producing an IFN-α productioninhibitor.

20. Use of a compound according to any one of Items 1 to 10, an opticalisomer thereof, or a salt thereof, for producing an IL-4 productioninhibitor.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is described below in further detail.

(I) Compound Represented by Formula (1)

In Formula (1), R1 represents a di-C₁₋₆ alkoxyphenyl group, i.e., aphenyl group substituted with two C₁₋₆ straight- or branched-chainalkoxy groups. Specific examples include 2,3-dimethoxyphenyl,2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl,3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,3-diethoxyphenyl,2,4-diethoxyphenyl, 2,5-diethoxyphenyl, 2,6-diethoxyphenyl,3,4-diethoxyphenyl, 3,5-diethoxyphenyl, 2,3-dipropoxyphenyl,2,4-dipropoxyphenyl, 2,5-dipropoxyphenyl, 2,6-dipropoxyphenyl,3,4-dipropoxyphenyl, 3,5-dipropoxyphenyl, 2,3-diisopropoxyphenyl,2,4-diisopropoxyphenyl, 2,5-diisopropoxyphenyl, 2,6-diisopropoxyphenyl,3,4-diisopropoxyphenyl, 3,5-diisopropoxyphenyl, 2,3-dibutoxyphenyl,2,4-dibutoxyphenyl, 2,5-dibutoxyphenyl, 2,6-dibutoxyphenyl,3,4-dibutoxyphenyl, 3,5-dibutoxyphenyl, 2,3-dipentoxyphenyl,2,4-dipentoxyphenyl, 2,5-dipentoxyphenyl, 2,6-dipentoxyphenyl,3,4-dipentoxyphenyl, 3,5-dipentoxyphenyl, 2,3-dihexyloxyphenyl,2,4-dihexyloxyphenyl, 2,5-dihexyloxyphenyl, 2,6-dihexyloxyphenyl,3,4-dihexyloxyphenyl, 3,5-dihexyloxyphenyl and the like. R1 in Formula(1) is preferably a 3,4-di-C₁₋₆ alkoxyphenyl group, more preferably a3,4-di-C₁₋₃ alkoxyphenyl group, and especially preferably a3,4-dimethoxyphenyl group or a 3,4-diethoxyphenyl group.

In Formula (1), R2 represents (a) a phenyl group, (b) a naphthyl group,(c) a pyridyl group, (d) a furyl group, (e) a thienyl group, (f) anisoxazolyl group, (g) a thiazolyl group, (h) a pyrrolyl group, (i) animidazolyl group, (j) a tetrazolyl group, (k) a pyrazinyl group, (l) athienothienyl group, (m) a benzothienyl group, (n) an indolyl group, (o)a benzimidazolyl group, (p) an imidazolyl group, (q) a quinolyl group,(r) a 3,4-dihydrocarbostyryl group, (s) a quinoxalinyl group, or (t) a1,3-benzodioxolyl group.

When R2 is (a) a phenyl group, the phenyl ring of the phenyl group maybe substituted with one or more members selected from the groupconsisting of (a-1) hydroxy groups, (a-2) halogen atoms, (a-3)unsubstituted or halogen-unsubstituted C₁₋₆ alkyl groups, (a-4)unsubstituted or halogen-substituted C₁₋₆ alkoxy groups, (a-5) C₁₋₆alkoxy-C₁₋₆ alkoxy groups, (a-6) amino-C₁₋₆ alkoxy groups which may besubstituted with a C₁₋₆ alkyl group or groups, (a-7) methylenedioxygroups, (a-8) carboxyl groups, (a-9) phenoxy groups, (a-10) C₁₋₆alkoxycarbonyl groups, (a-11) C₁₋₆ alkanoyloxy groups, (a-12) C₁₋₆alkanoyl groups, (a-13) cyano groups, (a-14) nitro groups, (a-15) C₁₋₆alkylcarbamoyl groups, (a-16) aminosulfonyl groups, (a-17) amino groupswhich may be substituted with a C₁₋₆ alkyl group or groups, (a-18) C₁₋₆alkanoylamino groups, (a-19) C₁₋₆ alkylthio groups, (a-20) phenylgroups, (a-21) pyrazolyl groups, (a-22) imidazolyl groups, (a-23)triazolyl groups, (a-24) morpholino groups, (a-25) pyrrolidinyl groups,and (a-26) piperazinylcarbonyl groups which may be substituted with aC₁₋₆ alkyl group or groups. When R2 is a substituted phenyl group, thenumber of substituents is not limited, and may be, for example, 1 to 5,and preferably 1 to 3.

When R2 is (c) a pyridyl group, the pyridine ring of the pyridyl groupmay be substituted with one or more members selected from the groupconsisting of (c-1) hydroxy groups, (c-2) C₁₋₆ alkyl groups, (c-3) C₁₋₆alkoxy groups, and (c-4) phenyl-C₁₋₆ alkoxy groups. When R2 is asubstituted pyridyl group, the number of substituents is not limited,and may be, for example, 1 to 4, and preferably 1 to 3.

When R2 is (d) a furyl group, the furan ring of the furyl group may besubstituted with a C₁₋₆ alkyl group or groups. When R2 is a substitutedfuryl group, the number of substituents is not limited, and may be, forexample, 1 to 3, and preferably 1 or 2.

When R2 is (e) a thienyl group, the thiophene ring of the thienyl groupmay be substituted with one or more members selected from the groupconsisting of (e-1) halogen atoms, (e-2) C₁₋₆ alkyl groups, and (e-3)C₁₋₆ alkoxy groups. When R2 is a substituted thienyl group, the numberof substituents is not limited, and may be, for example, 1 to 3, andpreferably 1 or 2.

When R2 is (f) an isooxazolyl group, the isooxazolyl ring of theisooxazolyl group may be substituted with a C₁₋₆ alkyl group or groups.When R2 is a substituted isooxazolyl group, the number of substituentsis not limited, and may be, for example, 1 or 2.

When R2 is (g) a thiazolyl group, the thiazole ring of the thiazolylgroup may be substituted with one or more members selected from thegroup consisting of (g-1) C₁₋₆ alkyl groups and (g-2) phenyl groupswhich may be substituted with a C₁₋₆ alkoxy group or groups. When R2 isa substituted thiazolyl group, the number of substituents is notlimited, and may be, for example, 1 to 2.

When R2 is (h) a pyrrolyl group, the pyrrole ring of the pyrrolyl groupmay be substituted with a C₁₋₆ alkyl group or groups. When R2 is asubstituted pyrrolyl group, the number of substituents is not limited,and may be, for example, 1 to 4, and preferably 1 or 2.

When R2 is (i) an imidazolyl group, the imidazole ring of the imidazolylgroup may be substituted with a C₁₋₆ alkyl group or groups. When R2 is asubstituted imidazolyl group, the number of substituents is not limited,and may be, for example, 1 to 3, and preferably 1 or 2.

When R2 is (o) a benzimidazolyl group, the benzimidazole ring of thebenzimidazolyl group may be substituted with a C₁₋₆ alkyl group orgroups. When R2 is a substituted benzimidazolyl group, the number ofsubstituents is not limited, and may be, for example, 1 to 5, andpreferably 1 to 3.

When R2 is (n) an indolyl group, the indole ring of the indolyl groupmay be substituted with a C₁₋₆ alkyl group or groups. When R2 is asubstituted indolyl group, the number of substituents is not limited,and may be, for example, 1 to 6, and preferably 1 to 3.

When R2 is (r) a 1,2,3,4-tetrahydroquinolyl group, the1,2,3,4-tetrahydroquinoline ring of the 1,2,3,4-tetrahydroquinolyl groupmay be substituted with an oxo group or groups. When R2 is anoxo-substituted 1,2,3,4-tetrahydroquinolyl group, the number of oxogroups is not limited, and may be, for example, 1 to 3, and preferably 1or 2.

The terms used in the description of the groups represented by R2 inFormula (1) are defined as follows.

Halogen atoms include fluorine atoms, chlorine atoms, bromine atoms,iodine atoms and the like.

C₁₋₆ alkyl groups are straight- or branched-chain alkyl groups with 1 to6 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl,isohexyl, 3-methylpentyl, etc.

Unsubstituted or halogen-substituted C₁₋₆ alkyl groups are straight- orbranched-chain alkyl groups with 1 to 6 carbon atoms as defined above,or such alkyl groups substituted with 1 to 7 halogen atoms. Examplesinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl,3-methylpentyl, fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, bromomethyl,dibromomethyl, dichlorofluoromethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, 2-chloroethyl, 3,3,3-trifluoropropyl,heptafluoropropyl, heptafluoroisopropyl, 3-chloropropyl, 2-chloropropyl,3-bromopropyl, 4,4,4-trifluorobutyl, 4,4,4,3,3-pentafluorobutyl,4-chlorobutyl, 4-bromobutyl, 2-chlorobutyl, 5,5,5-trifluoropentyl,5-chloropentyl, 6,6,6-trifluorohexyl, 6-chlorohexyl, etc.

C₁₋₆ alkoxy groups are groups composed of a C₁₋₆ alkyl group as definedabove and oxygen. Examples include methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy,neopentoxy, n-hexyloxy, isohexyloxy, 3-methylpentoxy, etc.

Unsubstituted or halogen-substituted C₁₋₆ alkoxy groups are C₁₋₆ alkoxygroups as defined above, or such alkoxy groups substituted with 1 to 7halogen atoms. Examples include methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, neopentoxy,n-hexyloxy, isohexyloxy, 3-methylpentoxy, fluoromethoxy,difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy,trichloromethoxy, bromomethoxy, dibromomethoxy, dichlorofluoromethoxy,2,2,2-trifluoroethoxy, pentafluoroethoxy, 2-chloroethoxy,3,3,3-trifluoropropoxy, heptafluoropropoxy, heptafluoroisopropoxy,3-chloropropoxy, 2-chloropropoxy, 3-bromopropoxy, 4,4,4-trifluorobutoxy,4,4,4,3,3-pentafluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy,2-chlorobutoxy, 5,5,5-trifluoropentoxy, 5-chloropentoxy,6,6,6-trifluorohexyloxy, 6-chlorohexyloxy, etc.

C₁₋₆ alkoxy-C₁₋₆ alkoxy groups are C₁₋₆ alkoxy groups substituted with 1to 7 C₁₋₆ alkoxy groups as defined above. Examples includemethoxymethoxy, 2-methoxyethoxy, 3-methoxypropoxy, 4-methoxybutoxy,5-methoxypentoxy, 6-methoxyhexyloxy, ethoxymethoxy, 1-ethoxyethoxy,2-ethoxyethoxy, 3-ethoxypropoxy, 2-isopropoxyethoxy, tert-butoxymethoxy,2-(tert-butoxy)ethoxy, 3-(tert-butoxy)propoxy, 6-(tert-butoxy)hexyloxy,4-(tert-butoxy)butoxy, etc.

Amino-C₁₋₆ alkoxy groups which may be substituted with a C₁₋₆ alkylgroup or groups are aminoalkoxy groups in which the alkoxy moiety is aC₁₋₆ straight- or branched-chain alkoxy group and in which 1 to 2 C₁₋₆alkyl groups may be substituted on the nitrogen atom. Examples of suchaminoalkoxy groups include aminomethoxy, 2-aminoethoxy, 1-aminoethoxy,3-aminopropoxy, 4-aminobutoxy, 5-aminopentyloxy, 6-aminohexyloxy,1,1-dimethyl-2-aminoethoxy, 2-methyl-3-aminopropoxy, methylaminomethoxy,1-ethylaminoethoxy, 2-propylaminoethoxy, 3-isopropylaminopropoxy,4-isopropylaminobutoxy, 4-butylaminobutoxy, 4-tert-butylaminobutoxy,5-pentylaminopentyloxy, 6-hexylaminohexyloxy, dimethylaminomethoxy,2-diethylaminoethoxy, 2-dimethylaminoethoxy,(N-ethyl-N-propylamino)methoxy, 2-(N-methyl-N-hexylamino)ethoxy, etc.

C₁₋₆ alkoxycarbonyl groups include, for example, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, and other C₁₋₆straight- or branched-chain alkoxycarbonyl groups.

C₁₋₆ alkanoyloxy groups include, for example, formyloxy, acetyloxy,propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy,tert-butylcarbonyloxy, hexanoyloxy, and other C₁₋₆ straight- orbranched-chain alkanoyloxy groups.

C₁₋₆ alkanoyl groups include, for example, formyl, acetyl, propionyl,butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanoyl, and otherC₁₋₆ straight- or branched-chain alkanoyl groups.

C₁₋₆ alkylcarbamoyl groups include, for example, methylcarbamoyl,ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl,tert-butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, and other C₁₋₆straight- or branched-chain alkylcarbamoyl groups.

Amino groups which may be substituted with a C₁₋₆ alkyl group or groupsinclude, for example, amino, methylamino, ethylamino, propylamino,isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino,dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino,dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino,N-methyl-N-butylamino, N-methyl-N-hexylamino, and other amino groupswhich may have 1 or 2 C₁₋₆ straight- or branched-chain alkyl groups assubstituents.

C₁₋₆ alkanoylamino groups include, for example, formylamino,acetylamino, propionylamino, butyrylamino, isobutyrylamino,pentanoylamino, tert-butylcarbonylamino, hexanoylamino, and other C₁₋₆straight- or branched-chain alkanoylamino groups.

C₁₋₆ alkylthio groups include, for example, methylthio, ethylthio,propylthio, isopropylthio, butylthio, tert-butylthio, pentylthio,hexylthio, and other C₁₋₆ straight- or branched-chain alkylthio groups.

Piperazinylcarbonyl groups which may be substituted with a C₁₋₆ alkylgroup or groups include, for example, piperazinylcarbonyl,methylpiperazinylcarbonyl, ethylpiperazinylcarbonyl,propylpiperazinylcarbonyl, isopropylpiperazinylcarbonyl,isopropylpiperazinylcarbonyl, butylpiperazinylcarbonyl,tert-butylpiperazinylcarbonyl, pentylpiperazinylcarbonyl,hexylpiperazinylcarbonyl, and other piperazinylcarbonyl groups which mayhave a C₁₋₆ straight- or branched-chain alkyl group or groups assubstituents.

Phenyl-C₁₋₆ alkoxy groups include, for example, benzyloxy, phenethyloxy,3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentoxy, 6-phenylhexyloxy, etc.

R2 in Formula (1) is preferably (a) a phenyl group, (c) a pyridyl group,(d) a furyl group, (e) a thienyl group, (g) a thiazolyl group, (h) apyrrolyl group or (i) an imidazolyl group, and more preferably (a) aphenyl group, (c) a pyridyl group or (g) a thiazolyl group.

In Formula (1), A is (i) —CO—B— wherein B is a C₁₋₆ alkylene group, (ii)—CO—Ba— wherein Ba is a C₂₋₆ alkenylene group, (iii) —CH(OH)—B— whereinB is as defined above,

(iv) —COCH(COOR3)-Bb- wherein R3 is a C₁₋₆ alkyl group and Bb is a C₁₋₆alkylene group, or (v) -Bc- wherein Bc is a C₂₋₆ alkylene group. In A inFormula (1), B, Ba or Bb is bound to the thiazole ring.

The terms used in the description of the groups represented by A inFormula (1) are defined as follows.

C₁₋₆ alkylene groups include, for example, methylene, ethylene,trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene,1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene,pentamethylene, hexamethylene and other C₁₋₆ straight- or branched-chainalkylene groups.

C₂₋₆ alkylene groups include, for example, ethylene, trimethylene,2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene,methylmethylene, ethylmethylene, tetramethylene, pentamethylene,hexamethylene and other C₁₋₆ straight- or branched-chain alkylenegroups.

C₂₋₆ alkenylene groups include, for example, vinylidene, propylene,butenylene and other C₁₋₆ straight- or branched-chain alkenylene groups.

The term “C₁₋₆ alkyl group” used in the description of A in Formula (1)has the same definition as used in the description of R2.

A in Formula (1) is preferably (i) —CO—B— wherein B is a methylenegroup, an ethylene group or a trimethylene group; (ii) —CO—Ba— whereinBa is a vinylidene group; (iii) —CH(OH)—B— wherein B is a methylenegroup or an ethylene group, (iv) —COCH(COOR3)-Bb- wherein R3 is a methylgroup, an ethyl group or a tert-butyl group and Bb is a methylene groupor a ethylene group; or (v) -Bc- wherein Bc is an ethylene group, atrimethylene group or a tetramethylene group; and more preferably, (i)—CO—B— wherein B is an ethylene group, (iii) —CH(OH)—B— wherein B is anethylene group, (iv) —COCH(COOR3)-Bb- wherein R3 is a methyl group andBb is a methylene group, or (v) -Bc- wherein Bc is a trimethylene group.

The compound represented by Formula (1) encompasses within its scope thefollowing Compounds (1-1) to (1-3):

Compound (1-1)

A compound in which R1 is a 3,4-di-C₁₋₆ alkoxyphenyl group, andpreferably a 3,4-dimethoxyphenyl group or a 3,4-diethoxyphenyl group;

R2 is (a) a phenyl group, (c) a pyridyl group, (d) a furyl group, (e) athienyl group, (g) a thiazolyl group, (h) a pyrrolyl group or (i) animidazolyl group; and

A is (i) —CO—B—, (ii) —CO—Ba—, (iii) —CH(OH)—B—, (iv) —COCH(COOR3)-Bb-or (v) -Bc-.

Compound (1-2)

A compound in which R1 is a 3,4-di-C₁₋₆ alkoxyphenyl group, andpreferably a 3,4-dimethoxyphenyl group or a 3,4-diethoxyphenyl group;

R2 is (a) a phenyl group, (c) a pyridyl group, (d) a furyl group, (e) athienyl group, (g) a thiazolyl group, (h) a pyrrolyl group or (i) animidazolyl group; and

A is (i) —CO—B— wherein B is a methylene group, an ethylene group or atrimethylene group, (ii) —CO—Ba— wherein Ba is a vinylidene group, (iii)—CH(OH)—B— wherein B is a methylene group or an ethylene group, (iv)—COCH(COOR3)-Bb- wherein R3 is a methyl group, an ethyl group or atert-butyl group, and Bb is a methylene group or an ethylene group, or(v) -Bc- wherein Bc is an ethylene group, a trimethylene group or atetramethylene group.

Compound (1-3)

A compound in which R1 is a 3,4-di-C₁₋₆ alkoxyphenyl group, andpreferably a 3,4-dimethoxyphenyl group or a 3,4-diethoxyphenyl group;

R2 is (a) a phenyl group, (c) a pyridyl group or (g) a thiazolyl group;and

A is (i) —CO—B— wherein B is ethylene, (iii) —CH(OH)—B— wherein B isethylene, (iv) —COCH(COOR3)-Bb- wherein R3 is a methyl group and Bb is amethylene group, or (v) -Bc- wherein Bc is a trimethylene group.

Some of the compounds represented by Formula (1) have optical isomers.Some of the compounds represented by Formula (1) and optical isomersthereof form acid addition salts or salts with bases. The presentinvention encompasses optical isomers of the compounds represented byFormula (1), as well as salts of the compounds represented by Formula(1) and optical isomers thereof.

Production Process for the Compound of Formula (1)

The compound of Formula (1), optical isomers thereof, and salts thereofcan be prepared by various synthetic processes selected according to thebasic skeleton, types of substituents, etc. Typical production processesfor the compound of Formula (1) are described below.

<Process 1>

In Process 1, the compound of Formula (1) is produced by reacting thecompound of Formula (2) with the compound of Formula (3).

wherein R1, R2 and A are as defined above; and X is a halogen atom.

A suitable ratio of the compound of Formula (3) to the compound ofFormula (2) is usually 0.5 to 5 mol, and preferably 0.5 to 3 mol, of thecompound of Formula (3) per mol of the compound of Formula (2).

The reaction of the compound of Formula (2) with the compound of Formula(3) is usually carried out in a suitable solvent. A wide variety ofknown solvents can be used as long as they do not hinder the reaction.Examples of usable solvents include dimethylformamide (DMF),dimethylsulfoxide (DMSO), acetonitrile and other aprotic polar solvents;acetone, methyl ethyl ketone and other ketone solvents; benzene,toluene, xylene, tetralin, liquid paraffin and other hydrocarbonsolvents; methanol, ethanol, isopropanol, n-butanol, tert-butanol andother alcohol solvents; tetrahydrofuran (THF), dioxane, dipropyl ether,diethyl ether, dimethoxyethane, diglyme and other ether solvents; ethylacetate, methyl acetate and other ester solvents; mixtures thereof; etc.Such solvents may contain water.

The reaction of the compound of Formula (2) with the compound of Formula(3) is usually performed by continuing stirring at −20 to 200° C., andpreferably at 0 to 150° C., for 30 minutes to 60 hours, and preferablyfor 1 to 30 hours.

The compound of Formula (3) used as a starting material is a knowncompound. Formula (2) encompasses novel compounds. Production processesfor the compounds are described hereinafter.

The reaction mixture obtained by the above reaction is, for example,cooled and subjected to an isolation procedure, such as filtration,concentration, extraction and/or the like, to separate a crude reactionproduct, which is further subjected, as required, to a conventionalpurification procedure, such as column chromatography, recrystallizationand/or the like, to thereby isolate and purify the compound of Formula(1).

<Process 2>

In Process 2, the compound of Formula (4) is reacted with the compoundof Formula (5) in the presence of a basic compound, to produce thecompound of Formula (1) wherein A is —COCH(COOR3)-Bb- (hereinafterreferred to as “Compound (1a)”).

wherein R1, R2, R3 and Bb are as defined above; and R4 is a C₁₋₆ alkylgroup.

The ratio of the compound of Formula (5) to the compound of Formula (4)is usually 0.5 to 5 mol, and preferably 0.5 to 3 mol, of the compound ofFormula (5) per mol of the compound of Formula (4).

The reaction of the compound of Formula (4) with the compound of Formula(5) is usually carried out in a suitable solvent. A wide variety ofknown solvents can be used as long as they do not hinder the reaction.Examples of usable solvents include dimethylformamide (DMF),dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and other aproticpolar solvents; benzene, toluene, xylene, tetralin, liquid paraffin andother hydrocarbon solvents; methanol, ethanol, isopropanol, n-butanol,tert-butanol and other alcohol solvents; tetrahydrofuran (THF), dioxane,dipropyl ether, diethyl ether, dimethoxyethane, diglyme and other ethersolvents; mixtures thereof; etc. Such solvents may contain water.

The reaction of the compound of Formula (4) with the compound of Formula(5) is usually carried out by continuing stirring at 0 to 200° C., andpreferably at room temperature to 150° C., for 30 minutes to 60 hours,and preferably 1 to 50 hours.

A wide variety of known basic compounds are usable, including, forexample, alkali metals, metal hydrides, metal alkoxides, carbonates,hydrogencarbonates and other inorganic basic compounds; acetate andother organic basic compounds; etc.

Examples of alkali metals include lithium, sodium, potassium, etc.Examples of metal hydrides include sodium hydride, potassium hydride,etc. Examples of metal alkoxides include sodium methoxide, sodiumethoxide, potassium tert-butoxide, sodium tert-butoxide, etc. Examplesof carbonates include sodium carbonate, potassium carbonate, etc.Examples of hydrogencarbonates include sodium hydrogencarbonate,potassium hydrogencarbonate, etc. Inorganic basic compounds furtherinclude sodium amide, lithium diisopropylamide, lithiumhexamethyldisilazide, sodium hexamethyldisilazide, n-butyl lithium,sec-butyl lithium, methyl lithium, etc.

Examples of acetates include sodium acetate, potassium acetate, etc.Other examples of organic basic compounds include triethylamine,trimethylamine, diisopropylethylamine, pyridine, dimethylaniline,1-methylpyrrolidine, N-methylmorpholine,1,5-diazabicyclo-[4.3.0]nonene-5 (DBN),1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO),2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine(BEMP), etc.

Such a basic compound is used in an amount of usually 0.1 to 5 mol, andpreferably 0.5 to 3 mol per mol of the compound of Formula (5).

The reaction mixture obtained by the above reaction is, for example,cooled and subjected to an isolation procedure, such as filtration,concentration, extraction and/or the like, to separate a crude reactionproduct, which is further subjected, as required, to a conventionalpurification procedure, such as column chromatography, recrystallizationand/or the like, to thereby isolate and purify the Compound (1a).

<Process 3>

In Process 3, the compound of Formula (1) in which A is —COCH(COOR3)-Bb-(Compound (1a)) is hydrolyzed and decarboxylated to produce the compoundof Formula (1) in which A is —CO—B— (hereinafter referred to as“Compound (1b)”).

wherein R1, R2, R3, B and Bb are as defined as above.

The hydrolysis and decarboxylation of Compound (1a) is carried out underacidic conditions. For example, an acid is added to a suspension orsolution of Compound (1a) in a suitable solvent, and the resultingmixture was stirred at 0 to 120° C. Usable solvents include water,alcohol solvents such as methanol, ethanol, isopropanol, ethyleneglycol, etc., acetonitrile, acetone, toluene, DMF, DMSO, acetic acid,trifluoroacetic acid, mixtures thereof, etc. Usable acids includetrifluoroacetic acid, acetic acid and other organic acids; hydrochloricacid, bromic acid, hydrobromic acid, sulfuric acid and other inorganicacids; etc. An organic acid such as trifluoroacetic acid, acetic acid orthe like can also be used as a reaction solvent. The reactiontemperature is usually 0 to 120° C., preferably room temperature to 100°C., and more preferably room temperature to 80° C. The reaction time isusually 30 minutes to 24 hours, preferably 30 minutes to 12 hours, andmore preferably 1 to 8 hours.

The reaction mixture obtained by the above reaction is, for example,cooled and subjected to an isolation procedure, such as filtration,concentration, extraction and/or the like, to separate a crude reactionproduct, which is further subjected, as required, to a conventionalpurification procedure, such as column chromatography, recrystallizationand/or the like, to thereby isolate and purify the Compound (1b).

<Process 4>

In Process 4, the compound of Formula (6) is reacted with the compoundof Formula (7) to produce the compound of Formula (1) in which A is—CO—B— (hereinafter referred to as “Compound (1b)”).

wherein R1, R2 and B are as defined above; R5 is a C₁₋₆ alkoxy group orCH₃ON(CH₃)—; M is a lithium atom or —MgX; and X is a halogen atom.

The ratio of the compound of Formula (7) to the compound of Formula (6)is usually 0.5 to 5 mol, and preferably 0.5 to 3 mol of the compound ofFormula (7) per mol of the compound of Formula (6).

The reaction of the compound of Formula (6) with the compound of Formula(7) is usually performed in a suitable solvent, which can be selectedfrom a wide variety of known solvents, as long as the solvent does nothinder the reaction. Examples of such solvents include benzene, toluene,xylene, tetralin, liquid paraffin and other hydrocarbon solvents;tetrahydrofuran (THF), dioxane, dipropyl ether, diethyl ether,dimethoxyethane, diglyme and other ether solvents; mixtures thereof;etc.

The reaction of the compound of Formula (6) with the compound of Formula(7) is usually performed by continuing stirring at −100 to 200° C., andpreferably at −100 to 100° C., for 30 minutes to 60 hours, andpreferably 1 to 50 hours.

The reaction mixture obtained by the above reaction is, for example,cooled and subjected to an isolation procedure, such as filtration,concentration, extraction and/or the like, to separate a crude reactionproduct, which is further subjected, as required, to a conventionalpurification procedure, such as column chromatography, recrystallizationand/or the like, to thereby isolate and purify the Compound (1b).

<Process 5>

In Process 5, the compound of Formula (1b) is reacted in the presence ofa reducing agent to produce the compound of Formula (1) in which A is—CH(OH)—B— (hereinafter referred to as “Compound (1c)”).

wherein R1, R2 and B are as defined above.

Examples of solvents usable in the above reaction include water;methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycoland other lower alcohols; ethyl acetate, methyl acetate and other estersolvents; diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglymeand other ethers; benzene, toluene, xylene and other aromatichydrocarbons; dichloromethane, dichloroethane, chloroform, carbontetrachloride and other halogenated hydrocarbons; mixtures thereof; etc.

Examples of usable reducing agents include sodium borohydride, lithiumaluminium hydride, diisobutylaluminum hydride and other hydride reducingagents, and mixtures of such hydride reducing agents.

When a hydride reducing agent is used as a reducing agent, a suitablereaction temperature is usually about −80 to about 100° C., andpreferably about −80 to about 70° C., and the reaction is completed inabout 30 minutes to about 100 hours. The amount of the hydride reducingagent to be used is usually about 1 to about 20 mol, and preferablyabout 1 to about 6 mol per mol of Compound (1b). In particular, whenlithium aluminium hydride is used as a reducing agent, it is preferredto use as a solvent an ether, such as diethyl ether, tetrahydrofuran,dioxane, monoglyme, diglyme or the like, or an aromatic hydrocarbon,such as benzene, toluene, xylene or the like.

The reaction mixture obtained by the above reaction is, for example,cooled and subjected to an isolation procedure, such as filtration,concentration, extraction and/or the like, to separate a crude reactionproduct, which is further subjected, as required, to a conventionalpurification procedure, such as column chromatography, recrystallizationand/or the like, to thereby isolate and purify the Compound (1c).

<Process 6>

In Process 6, the compound of Formula (6) is reacted with the compoundof Formula (8) to produce Compound (1c).

wherein R1, R2, B and M are as defined above.

The reaction in Process 6 is performed under the same reactionconditions as for the reaction in Process 4.

<Process 7>

In Process 7, Compound (1c) is reacted in a suitable solvent in thepresence of an oxidizing agent to produce Compound (1b).

wherein R1, R2 and B are as defined above.

The solvent for use in Process 7 can be selected from a wide variety ofknown solvents, as long as it does not hinder the reaction. Examples ofusable solvents include dimethylformamide (DMF), dimethyl sulfoxide(DMSO), N-methylpyrrolidone (NMP), acetonitrile and other aprotic polarsolvents; benzene, toluene, xylene, tetralin, liquid paraffin and otherhydrocarbon solvents; ethyl acetate, methyl acetate and other estersolvents; tetrahydrofuran (THF), dioxane, dipropyl ether, diethyl ether,dimethoxyethane, diglyme and other ether solvents; dichloromethane,dichloroethane, chloroform, carbon tetrachloride and other halogenatedhydrocarbons; mixtures thereof; etc. Such solvents may contain water.

In Process 7, the oxidizing agent can selected from a wide variety ofknown oxidizing agents. Examples of usable oxidizing agents includedimethyl sulfoxide (DMSO)-sulfur trioxide-pyridine, dimethyl sulfoxide(DMSO)-oxalyl chloride-triethylamine, pyridinium chlorochromate (PCC),chromic acid, manganese dioxide, etc.

The amount of oxidizing agent to be used is usually about 1 about 20mol, and preferably about 1 to about 6 mol per mol of Compound (1c).

The reaction mixture obtained by the above reaction is, for example,cooled and subjected to an isolation procedure, such as filtration,concentration, extraction and/or the like, to separate a crude reactionproduct, which is further subjected, as required, to a conventionalpurification procedure, such as column chromatography, recrystallizationand/or the like, to thereby isolate and purify the Compound (1b).

<Process 8>

In Process 8, the compound of Formula (8) is reacted with the compoundof Formula (9) in the presence of a basic compound to produce thecompound of Formula (1) in which A is —CO—Ba— (hereinafter referred toas “Compound (1d)”).

wherein R1, R2 and Ba are as defined above; R6 is a hydrogen atom or—PO(OR7)₂; Bd is —(CH₂)n—; n is an integer from 0 to 4; and R7 is a C₁₋₆alkyl group.

The ratio of the compound of Formula (9) to the compound of Formula (8)is usually 0.5 to 5 mol, and preferably 0.5 to 3 mol of the compound ofFormula (9) per mol of the compound of Formula (8).

The reaction of the compound of Formula (8) with the compound of Formula(9) is usually carried out in a suitable solvent. A wide variety ofknown solvents can be used as long as they do not hinder the reaction.Examples of usable solvents include dimethylformamide (DMF),dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and other aproticpolar solvents; benzene, toluene, xylene, tetralin, liquid paraffin andother hydrocarbon solvents; methanol, ethanol, isopropanol, n-butanol,tert-butanol and other alcohol solvents; tetrahydrofuran (THF), dioxane,dipropyl ether, diethyl ether, dimethoxyethane, diglyme and other ethersolvents; mixtures thereof; etc. Such solvents may contain water.

The reaction of the compound of Formula (8) with the compound of Formula(9) is usually carried out by continuing stirring at 0 to 200° C., andpreferably at room temperature to 150° C., for 30 minutes to 60 hours,and preferably 1 to 50 hours.

A wide variety of known basic compounds are usable, including, forexample, alkali metals, metal hydrides, metal alkoxides, carbonates,hydrogencarbonates and other inorganic basic compounds; acetates andother organic basic compounds; etc.

Examples of alkali metals include lithium, sodium, potassium, etc.Examples of metal hydrides include sodium hydride, potassium hydride,etc. Examples of metal alkoxides include sodium methoxide, sodiumethoxide, potassium tert-butoxide, sodium tert-butoxide, etc. Examplesof carbonates include sodium carbonate, potassium carbonate, etc.Examples of hydrogencarbonates include sodium hydrogencarbonate,potassium hydrogencarbonate, etc. Inorganic basic compounds include, inaddition to the above compounds, sodium amide, lithium diisopropylamide,lithium hexamethyldisilazide, sodium hexamethyldisilazide, etc.

Examples of acetates include sodium acetate, potassium acetate, etc.Examples of organic basic compounds other than the above includetriethylamine, trimethylamine, diisopropylethylamine, pyridine,dimethylaniline, 1-methylpyrrolidine, N-methylmorpholine,1,5-diazabicyclo[4.3.0]nonene-5 (DBN),1,8-diazabicyclo[5.4.0]-undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO),2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphospholine(BEMP), etc.

It is suitable to use such a basic compound in an amount of 0.1 to 5mol, preferably 0.5 to 3 mol per mol of the compound represented byFormula (8).

The reaction mixture obtained by the above reaction is, for example,cooled and subjected to an isolation procedure, such as filtration,concentration, extraction and/or the like, to separate a crude reactionproduct, which is further subjected, as required, to a conventionalpurification procedure, such as column chromatography, recrystallizationand/or the like, to thereby isolate and purify the Compound (1d).

<Process 9>

In Process 9, Compound (1d) is reacted in the presence of a reducingagent to produce Compound (1b).

wherein R1, R2, Ba and B are as defined above.

Examples of reducing agents include hydrogen catalytic reducing agents,such as palladium-black, palladium-carbon, platinum oxide, platinumblack, Raney nickel, etc.

When using a hydrogen catalytic reducing agent, it is usually suitableto perform the reaction in an hydrogen atmosphere at atmospheric normalpressure to about 20 atm, and preferably at atmospheric normal pressureto about 10 atm, or in the presence of a hydrogen donor, such as formicacid, ammonium formate, cyclohexene, hydrazine hydrate or the like,usually at about −30 to about 100° C., and preferably at about 0 toabout 60° C. The reaction is usually completed in about 1 to about 12hours. A suitable amount of the hydrogen catalytic reducing agent to beused is usually about 0.1 to about 40 parts by weight, and preferablyabout 1 to about 20 parts by weight, per 100 parts by weight of Compound(1d).

Examples of solvents usable in the reaction in Process 9 include water;methanol, ethanol, isopropanol, n-butanol, tert-butanol, ethylene glycoland other lower alcohols; ethyl acetate, methyl acetate and other estersolvents; dimethylformamide (DMF), N-methylpyrrolidone (NMP) and otheraprotic polar solvents; diethyl ether, tetrahydrofuran, dioxane,monoglyme, diglyme and other ethers; benzene, toluene, xylene and otheraromatic hydrocarbons; mixtures thereof; etc.

The reaction mixture obtained by the above reaction is, for example,cooled and subjected to an isolation procedure, such as filtration,concentration, extraction and/or the like, to separate a crude reactionproduct, which is further subjected, as required, to a conventionalpurification procedure, such as column chromatography, recrystallizationand/or the like, to thereby isolate and purify the Compound (1b).

<Process 10>

In Process 10, Compound (1b) is subjected to a reduction reaction toproduce the compound of Formula (1e) (hereinafter referred to as“Compound (1e)”).

wherein R1, R2 and B are as defined above; and Bc is a C₂₋₆ alkylenegroup.

A wide variety of known reduction reactions can be employed as the abovereduction reaction. For example, the reduction reaction can be performedby heating the compound in the presence of hydrazine and a basiccompound in a suitable solvent.

Examples of usable solvents include water; methanol, ethanol,isopropanol, butanol, tert-butanol, ethylene glycol, diethylene glycoland other lower alcohols; dimethylformamide (DMF), N-methylpyrrolidone(NMP) and other aprotic polar solvents; diethyl ether, tetrahydrofuran,dioxane, monoglyme, diglyme and other ethers; benzene, toluene, xyleneand other aromatic hydrocarbons; mixtures thereof; etc.

A wide variety of known basic compounds are usable, which include, forexample, metal hydrides, metal alkoxides, hydroxides, carbonates,hydrogencarbonates and other inorganic basic compounds, etc.

Examples of metal hydrides include sodium hydride, potassium hydride,etc. Examples of metal alkoxides include sodium methoxide, sodiumethoxide, potassium tert-butoxide, etc. Examples of hydroxides includesodium hydroxide, potassium hydroxide, etc. Examples of carbonatesinclude sodium carbonate, potassium carbonate, etc. Examples ofhydrogencarbonates include sodium hydrogencarbonate, potassiumhydrogencarbonate, etc. Inorganic basic compounds include, besides theabove compounds, sodium amide and the like.

It is usually suitable to use such a basic compound in an amount of 0.1to 2 mol, preferably 0.1 to 1 mol, and more preferably 0.1 to 0.5 molper mol of Compound (1b).

A suitable reaction temperature is usually about 50 to about 250° C.,and preferably about 100 to about 200° C., and the reaction is completedusually in about 30 minutes to about 10 hours.

The reaction mixture thus obtained is, for example, cooled and subjectedto an isolation procedure, such as filtration, concentration, extractionand/or the like, to separate a crude reaction product, which is furthersubjected, as required, to a conventional purification procedure, suchas column chromatography, recrystallization and/or the like, to therebyisolate and purify the Compound (1e).

<Process 11>

In Process 11, a halogen atom in the compound of Formula (1f)(hereinafter referred to as “Compound (1f)”) is substituted by cyano toproduce the compound of Formula (1g) (hereinafter referred to as“Compound (1g)”).

wherein R1, A and X are as defined above; R8 is a hydroxy group, anunsubstituted or halogen-substituted C₁₋₆ alkyl group, an unsubstitutedor halogen-substituted C₁₋₆ alkoxy group, a C₁₋₆ alkoxy-C₁₋₆ alkoxygroup, a phenyl-C₁₋₆ alkoxy group, an amino-C₁₋₆ alkoxy group which maybe substituted with a C₁₋₆ alkyl group, a methylenedioxy group, acarboxyl group, a phenoxy group, a C₁₋₆ alkoxycarbonyl group, C₁₋₆alkanoyloxy group, a C₁₋₆ alkanoyl group, a cyano group, a nitro group,a C₁₋₆ alkylcarbamoyl group, an aminosulfonyl group, an amino groupwhich may be substituted with a C₁₋₆ alkyl group or groups, a C₁₋₆alkanoylamino group, a C₁₋₆ alkylthio group, a phenyl group, a pyrazolylgroup, an imidazolyl group, a triazolyl group, a morpholino group, apyrrolidinyl group, or a piperazinylcarbonyl group which may besubstituted with a C₁₋₆ alkyl group or groups; and m is an integer from0 to 4.

A wide variety of known substitution reactions can be employed as theabove substitution reaction. For example, the substitution reaction canbe performed by heating the compound with a cyanide in the presence of apalladium catalyst in a suitable solvent.

Examples of palladium catalysts include tetrakistriphenylphosphinepalladium and the like. A suitable amount of palladium catalyst isusually about 0.001 to about 0.4 mol, and preferably about 0.001 toabout 0.2 mol per mol of Compound (1f).

Examples of cyanides include zinc (II) cyanide and the like. It isusually suitable to use such a cyanide in an amount of 0.1 to 5 mol,preferably 0.5 to 3 mol, and more preferably 0.5 to 1 mol per mol ofCompound (1f).

The solvent can be selected from a wide variety of known solvents, aslong as it does not hinder the reaction. Examples of usable solventsinclude dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrileand other aprotic polar solvents; acetone, methyl ethyl ketone and otherketone solvents; benzene, toluene, xylene, tetralin, liquid paraffin andother hydrocarbon solvents; methanol, ethanol, isopropanol, n-butanol,tert-butanol and other alcohol solvents; tetrahydrofuran (THF), dioxane,dipropyl ether, diethyl ether, diglyme and other ether solvents; ethylacetate, methyl acetate and other ester solvents; mixtures thereof; etc.Such solvents may contain water.

The reaction of the Compound (1f) with a cyanide is usually carried outat −100 to 200° C., and preferably at −100 to 100° C., for 30 minutes to60 hours, and preferably 1 to 50 hours.

The reaction mixture thus obtained is, for example, cooled and subjectedto an isolation procedure, such as filtration, concentration, extractionand/or the like, to separate a crude reaction product, which is furthersubjected, as required, to a conventional purification procedure, suchas column chromatography, recrystallization and/or the like, to therebyisolate and purify the Compound (1g).

<Process 12>

In Process 12, the carboxylic acid moiety of the compound of Formula(1h) (hereinafter referred to as “Compound (1h)”) is subjected to anamide bond formation reaction with the compound of Formula (10)(hereinafter referred to as “Compound 10”) to produce the compound ofFormula (1i) (hereinafter referred to as “Compound (1i)”).

wherein R1, A and m are as defined above; R9 is a hydroxy group, ahalogen atom, an unsubstituted or halogen-substituted C₁₋₆ alkyl group,an unsubstituted or halogen-substituted C₁₋₆ alkoxy group, a C₁₋₆alkoxy-C₁₋₆ alkoxy group, a phenyl-C₁₋₆ alkoxy group, an amino-C₁₋₆alkoxy group which may be substituted with a C₁₋₆ alkyl group or groups,a methylenedioxy group, a phenoxy group, a C₁₋₆ alkoxycarbonyl group, aC₁₋₆ alkanoyloxy group, a C₁₋₆ alkanoyl group, a cyano group, a nitrogroup, a C₁₋₆ alkylcarbamoyl group, an aminosulfonyl group, an aminogroup which may be substituted with a C₁₋₆ alkyl group, a C₁₋₆alkanoylamino group, a C₁₋₆ alkylthio group, a phenyl group, a pyrazolylgroup, an imidazolyl group, a triazolyl group, a morpholino group, apyrrolidinyl group or a piperazinylcarbonyl group which may besubstituted by a C₁₋₆ alkyl group or groups; m is an integer from 0 to4; and R10 and R11 are independently each a hydrogen atom or a C₁₋₆alkyl group, and may be bonded to each other via the adjacent nitrogenatom and a carbon atom or atoms or another nitrogen atom, to form apiperazine ring which may be substituted with a C₁₋₆ alkyl group orgroups.

Conditions for known amide bond formation reactions can be employed inthe amide formation reaction in Process 12. For example, the followingreaction methods can be employed: (A) a mixed acid anhydride method, inwhich carboxylic acid (1h) is reacted with an alkyl halocarboxylate toform a mixed acid anhydride, which is then reacted with Compound (10);(B) an active ester method, in which carboxylic acid (1h) is convertedto an activated ester, such as a phenyl ester, p-nitrophenyl ester,N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester or the like, oran activated amide with benzoxazoline-2-thione, and the activated esteror amide is reacted with Compound (10); (C) a carbodiimide method, inwhich carboxylic acid (1h) is subjected to a condensation reaction withCompound (10) in the presence of an activating agent, such asdicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(WSC), carbonyldiimidazole or the like; (D) other methods, for example,a method in which carboxylic acid (1h) is converted to a carboxylicanhydride using a dehydrating agent such as acetic anhydride, and thecarboxylic anhydride is then reacted with Compound (10), or a method inwhich an ester of carboxylic acid (1h) with a lower alcohol is reactedwith Compound (10) at a high pressure and a high temperature, a methodin which an acid halide of carboxylic acid (1h), i.e., a carboxylic acidhalide, is reacted with Compound (10); etc.

The mixed acid anhydride used in the mixed acid anhydride method (A) canbe obtained by the known Schotten-Baumann reaction, and the obtainedmixed acid anhydride is reacted with Compound (10), usually withoutbeing isolated, to thereby produce the Compound (1i). TheSchotten-Baumann reaction is performed in the presence of a basiccompound. Usable basic compounds include compounds conventionally usedin the Schotten-Baumann reaction, such as triethylamine, trimethylamine,pyridine, dimethylaniline, N-ethyldiisopropylamine,dimethylaminopyridine, N-methylmorpholine,1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7(DBU), 1,4-diazabicyclo[2.2.2]-octane (DABCO) and other organic bases;sodium carbonate, potassium carbonate, sodium hydrogencarbonate,potassium hydrogencarbonate and other carbonates; sodium hydroxide,potassium hydroxide, calcium hydroxide and other metal hydroxides;potassium hydride, sodium hydride, potassium, sodium, sodium amide,metal alkoxides such as sodium methoxide and sodium ethoxide, and otherinorganic bases; etc. The reaction is usually performed at about −20 toabout 100° C., and preferably at about 0 to about 50° C., usually forabout 5 minutes to about 10 hours, and preferably for about 5 minutes toabout 2 hours. The reaction of the obtained mixed acid anhydride withCompound (10) is usually carried out at about −20 to about 150° C., andpreferably at about 10 to about 50° C., usually for about 5 minutes toabout 10 hours, and preferably for about 5 minutes to about 5 hours.Generally, the mixed acid anhydride method is performed in a solvent.Solvents used for conventional mixed acid anhydride methods are usable.Examples of usable solvents include chloroform, dichloromethane,dichloroethane, carbon tetrachloride and other halogenated hydrocarbons;benzene, toluene, xylene and other aromatic hydrocarbons; diethyl ether,diisopropyl ether, tetrahydrofuran, dimethoxyethane and other ethers;methyl acetate, ethyl acetate, isopropyl acetate and other esters;N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide,hexamethylphosphoric triamide and other aprotic polar solvents; mixturesthereof; etc. Examples of alkyl halocarboxylates usable in the mixedacid anhydride method include methyl chloroformate, methyl bromoformate,ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, etc. Inthis method, Compound (1h), an alkyl halocarboxylate and Compound (10)are preferably used in equimolar amounts, but each of the alkylhalocarboxylate and Compound (1h) can also be used in an amount of about1 to about 1.5 mol per mol of Compound (10).

Method (C), in which a condensation reaction is carried out in thepresence of an activating agent, can be performed in a suitable solventin the presence or absence of a basic compound. Solvents and basiccompounds usable in this method include those mentioned hereinafter assolvents and basic compounds usable in the method in which a carboxylicacid halide is reacted with Compound (10) mentioned above as one of theother methods (D). A suitable amount of activating agent is at least 1mol, and preferably 1 to 5 mol per mol of Compound (10). When using WSCas an activating agent, addition of 1-hydroxybenzotriazol to thereaction system enables the reaction to proceed advantageously. Thereaction is usually performed at about −20 to about 180° C., andpreferably at about 0 to about 150° C., and is usually completed inabout 5 minutes to about 90 hours.

When the method in which a carboxylic acid halide is reacted withCompound (10), mentioned above as one of the other methods (D), isemployed, the reaction is performed in the presence of a basic compoundin a suitable solvent. Usable basic compounds include a wide variety ofknown basic compounds, such as those for use in the Schotten-Baumannreaction described above. Usable solvents include, in addition to thoseusable in the mixed acid anhydride method, methanol, ethanol,isopropanol, propanol, butanol, 3-methoxy-1-butanol, ethylcellosolve,methylcellosolve and other alcohols; acetonitrile; pyridine; acetone;water; etc. The ratio of the carboxylic acid halide to Compound (10) isnot limited and can be suitably selected from a wide range. It isusually suitable to use, for example, at least about 1 mol, andpreferably about 1 to about 5 mol of the carboxylic acid halide per molof Compound (10). The reaction is usually performed at about −20 toabout 180° C., and preferably at about 0 to about 150° C., and usuallycompleted in about 5 minutes to about 50 hours.

The amide bond formation reaction in Process 12 can also be performed byreacting Compound (1h) with Compound (10) in the presence of aphosphorus compound serving as a condensing agent, such astriphenylphosphine, diphenylphosphinyl chloride,phenyl-N-phenylphosphoramide chloridate, diethyl chlorophosphate,diethyl cyanophosphate, diphenylphosphoric azide,bis(2-oxo-3-oxazolidinyl)phosphinic chloride or the like.

The reaction is carried out in the presence of a solvent and a basiccompound usable for the method in which a carboxylic acid halide isreacted with Compound (10), usually at about −20 to about 150° C., andpreferably at about 0 to about 100° C., and is usually completed inabout 5 minutes to about 30 hours. It is suitable to use each of thecondensing agent and Compound (1h) in amounts of at least about 1 mol,and preferably about 1 to about 2 mol per mol of Compound (10).

<Process 13>

In Process 13, the carboxylic acid moiety of Compound (1h) is subjectedto an ester bond formation reaction with the compound of Formula (11)(hereinafter referred to as “Compound (11)”) to produce the compound ofFormula (1j) (hereinafter referred to as “Compound 1j”).

wherein R1, R9, A and m are as defined above; R12 is a C₁₋₆ alkyl group;and Y is a hydroxy group or a halogen atom.

Conditions for known ester bond formation reactions can be employed. Forexample, when Y in Compound (11) is a hydroxy group, the ester bondformation reaction can be performed by heating Compound (1h) andCompound (11) in a suitable solvent in the presence of acid. Examples ofusable solvents include chloroform, dichloromethane, dichloroethane,carbon tetrachloride and other halogenated hydrocarbons; benzene,toluene, xylene and other aromatic hydrocarbons; diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and otherethers; methyl acetate, ethyl acetate, isopropyl acetate and otheresters; N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide,hexamethylphosphoric triamide and other aprotic polar solvents; mixturesthereof; etc. Compound (11) can also be used as a solvent. Examples ofusable acids include trifluoroacetic acid and other organic acids;hydrochloric acid, bromic acid, hydrobromic acid, sulfuric acid andother inorganic acids; etc. The reaction is usually performed at about 0to about 150° C., and preferably at about room temperature to about 100°C., and is usually completed in about 0.5 to about 30 hours.

When Y in Compound (11) is a halogen atom, the reaction in Process 13 isperformed by reacting Compound (11) with Compound (1h) in a suitablesolvent in the presence of a basic compound. Examples of usable solventsinclude methanol, ethanol, isopropanol, butanol, tert-butanol, ethyleneglycol, diethylene glycol and other lower alcohols; chloroform,dichloromethane, dichloroethane, carbon tetrachloride and otherhalogenated hydrocarbons; benzene, toluene, xylene and other aromatichydrocarbons; diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane, dimethoxyethane and other ethers; methyl acetate, ethylacetate, isopropyl acetate and other esters; N,N-dimethylacetamide,N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamideand other aprotic polar solvents; mixtures thereof; etc.

Examples of usable basic compounds include triethylamine,trimethylamine, pyridine, dimethylaniline, N-ethyldiisopropylamine,dimethylaminopyridine, N-methylmorpholine,1,5-diazabicyclo[4.3.0]nonene-5 (DBN),1,8-diazabicyclo-[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO) and other organic bases; sodium carbonate, potassium carbonate,sodium hydrogencarbonate, potassium hydrogencarbonate and othercarbonates; sodium hydroxide, potassium hydroxide, calcium hydroxide andother metal hydroxides; potassium hydride, sodium hydride, potassium,sodium, sodium amide, metal alkoxides such as sodium methoxide andsodium ethoxide, and other inorganic bases; etc. A suitable ratio ofCompound (1h) to Compound (11) is at least 1 mol, and preferably 1 to 5mol of Compound (1h) per mol of Compound (11). The reaction is usuallyperformed at about 0 to about −150° C., and preferably at about roomtemperature to about 100° C., and is usually completed in about 0.5hours to about 30 hours.

<Process 14>

In Process 14, the compound of Formula (1k) (hereinafter referred to as“Compound (1k)”) is alkylated with the compound of Formula (12)(hereinafter referred to as “Compound (12)”) to produce the compound ofFormula (11) (hereinafter referred to as “Compound 11”).

wherein R1, A and m are as defined above; R13 is a halogen atom, anunsubstituted or halogen-substituted C₁₋₆ alkyl group, an unsubstitutedor halogen-substituted C₁₋₆ alkoxy group, a C₁₋₆ alkoxy-C₁₋₆ alkoxygroup, a phenyl-C₁₋₆ alkoxy group, an amino-C₁₋₆ alkoxy group which maybe substituted with a C₁₋₆ alkyl group, a methylenedioxy group, acarboxyl group, a phenoxy group, a C₁₋₆ alkoxycarbonyl group, a C₁₋₆alkanoyloxy group, C₁₋₆ alkanoyl group, a cyano group, a nitro group, aC₁₋₆ alkylcarbamoyl group, an aminosulfonyl group, an amino group whichmay be substituted with a C₁₋₆ alkyl group or groups, a C₁₋₆alkanoylamino group, a C₁₋₆ alkylthio group, a phenyl group, a pyrazolylgroup, an imidazolyl group, a triazolyl group, a morpholino group, apyrrolidinyl group, or a piperazinylcarbonyl group which may besubstituted with a C₁₋₆ alkyl group or groups; R12 is a C₁₋₆ alkylgroup; Y is a hydroxy group, a halogen atom or —OSO₂—R13; R13 is a C₁₋₆alkyl group or a phenyl group in which the phenyl ring may besubstituted with a C₁₋₆ alkyl group or groups, a halogen atom or atomsor a nitro group or groups; R14 is a C₁₋₆ alkyl group or a C₁₋₆alkoxy-C₁₋₆ alkoxy group; and Ya is a halogen atom.

In Process 14, the alkylation reaction can be performed by reactingCompound (1k) with Compound (12), for example, in a suitable solvent inthe presence of a basic compound. Examples of usable solvents includemethanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol,diethylene glycol and other lower alcohols; chloroform, dichloromethane,dichloroethane, carbon tetrachloride and other halogenated hydrocarbons;benzene, toluene, xylene and other aromatic hydrocarbons; diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and otherethers; methyl acetate, ethyl acetate, isopropyl acetate and otheresters; N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide,hexamethylphosphoric triamide and other aprotic polar solvents; mixturesthereof; etc.

Examples of basic compounds include triethylamine, trimethylamine,pyridine, dimethylaniline, N-ethyldiisopropylamine,dimethylaminopyridine, N-methylmorpholine,1,5-diazabicyclo[4.3.0]nonene-5 (DBN),1,8-diazabicyclo[5.4.0]-undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO) and other organic bases; sodium carbonate, potassium carbonate,sodium hydrogencarbonate, potassium hydrogencarbonate and othercarbonates; metal hydroxides such as sodium hydroxide, potassiumhydroxide and calcium hydroxide; potassium hydride, sodium hydride,potassium, sodium, sodium amide, metal alkoxides such as sodiummethoxide and sodium ethoxide, and other inorganic bases; etc. Asuitable ratio of Compound (12) to Compound (1k) is at least 1 mol, andpreferably 1 to 5 mol of Compound (12) per mol of Compound (1k). Thereaction is usually performed at about 0 to about 150° C., andpreferably at about room temperature to about 100° C., and is usuallycompleted in about 0.5 to about 30 hours.

Production Process for Compound of Formula (2)

The compound of Formula (2) (hereinafter referred to as “Compound (2)”)for use as a starting material can be produced by, for example, thefollowing Process 15 or 16.

<Process 15>

In Process 15, the compound represented by Formula (13) (hereinafterreferred to as “Compound (13)”) is halogenated to produce Compound (2).

wherein R2, A and X are as defined above. The halogenation reaction ofCompound (13) can be performed in a suitable solvent in the presence ofa halogenating agent. Examples of usable halogenating agents includebromine, chlorine and other molecular halogens; iodine chloride;sulfuryl chloride; cupric bromide and other copper compounds;N-bromosuccinimide, N-chlorosuccinimide and other N-halogenatedsuccinimides; etc. Examples of usable solvents include dichloromethane,dichloroethane, chloroform, carbon tetrachloride and other halogenatedhydrocarbons; acetic acid; propionic acid and other fatty acids; carbondisulfide; etc. A suitable amount of halogenating agent is usually about1 to about 10 mol, and preferably about 1 to about 5 mol per mol ofCompound (13). The reaction is usually performed at about 0° C. to aboutthe boiling point of the solvent, and preferably at about 0 to about100° C., and is usually completed in about 5 minutes to about 20 hours.<Process 16>

In Process 16, the compound represented by Formula (14) (hereinafterreferred to as “Compound (14)”) is halogenated in the presence of waterunder acidic conditions to produce Compound (2).

wherein R2, A and X are as defined above. The halogenation reaction ofCompound (14) is performed in a suitable solvent in the presence of ahalogenating agent. Examples of usable halogenating agents includebromine, chlorine and other molecular halogens; iodine chloride;sulfuryl chloride; N-bromosuccinimide, N-chlorosuccinimide and otherN-halogenated succinimides; etc. Examples of usable solvents includehydrous acetonitrile. Examples of usable acids include hydrochloricacid, bromic acid, hydrobromic acid, sulfuric acid and other inorganicacids, and the like. A suitable amount of the halogenating agent isusually about 1 to about 10 mol, and preferably about 1 to about 5 molper mol of Compound (14). The reaction is usually performed at 0° C. tothe boiling temperature of the solvent, and preferably at about 0 toabout 100° C., and is usually completed in about 5 minutes to about 20hours.(II) Medicinal Effects and Uses

The compounds represented by Formula (1), optical isomers thereof andsalts thereof (hereinafter collectively referred to as “the compound ofthe present invention”) exhibit specific inhibitory activity againstPDE4, and thus are useful as active ingredients of PDE4 inhibitors.

The compound of the present invention, based on its specific inhibitoryactivity against PDE4, can be used as an active ingredient of apharmaceutical composition for use as a preventive or therapeutic agentfor various diseases. Examples of diseases on which preventive ortherapeutic effects are exhibited based on the specific inhibitoryactivity against PDE4 include acute or chronic (in particular,inflammatory and allergen-induced) respiratory tract diseases (e.g.,bronchial asthma and chronic obstructive pulmonary diseases) of variousorigins; dermatoses (in particular, proliferative, inflammatory andallergic types) (e.g., psoriasis vulgaris, toxic and allergic contacteczemas, atopic dermatitis, alopecia areata and other proliferative,inflammatory and allergic dermatoses); diseases related to nervousdysfunctions, such as of learning, memory and cognition disorders,caused due to Alzheimer's disease, Parkinson's disease, etc.; diseasesrelated to mental dysfunctions (e.g., manic-depressive psychosis,schizophrenia and anxiety syndrome); systemic or local joint diseases(e.g., knee osteoarthrosis and articular rheumatism); diffuseinflammation in the gastrointestinal region (e.g., Crohn's disease andulcerative colitis); allergic and/or chronic diseases in the upperrespiratory tract (pharyngeal cavity, nose) region and adjacent regions(paranasal sinus, eye) caused by improper immunological reactions (e.g.,allergic rhinitis/sinusitis, chronic rhinitis/sinusitis and allergicconjunctivitis); and other diseases. Among these, for atopic dermatitis,the compound of the present invention exhibits particularly highpreventive or therapeutic effects, and therefore can be suitably appliedto prevent or treat this disease.

When the compound of the present invention is employed as a PDE 4inhibitor or a preventive or therapeutic agent for diseases as mentionedabove, the compound can be used as an oral preparation, an injection, anexternal preparation or like preparation.

When used as an oral preparation, the compound can be formulated into apowder, tablets, granules, capsules, a syrup, films, troches, a liquidor like forms. The oral preparation may contain a pharmaceuticallyacceptable base and/or carrier, and pharmaceutically acceptableadditives, such as binders, disintegrators, lubricants, humectants,buffers, preservatives, flavors, etc., as required.

When used as an injection, the compound can be formulated into anaqueous solution or suspension obtained by dissolving or suspending thecompound in physiological saline, an aqueous glucose solution or thelike.

When used as an external preparation, the compound can be formulatedinto a liquid, oily preparation, lotion, liniment, milky lotion,suspension, cream, ointment or like forms. The external preparation maycontain a carrier, a base and/or additives that are conventionally usedin external preparations, as required. Examples of usable additivesinclude water, oils, surfactants, solubilizing components, emulsifiers,colorants (dyes, pigments), flavors, preservatives, antiseptics,thickeners, antioxidants, sequestering agents, pH modifiers,deodorizers, etc.

When the compound of the present invention is employed as a PDE4inhibitor or a preventive or therapeutic agent for the above diseases,the effective dosage amount and number of doses of the compound of thepresent invention vary depending on the type of the compound, the ageand weight of the subject to be given the compound, the symptom, thepurpose of use and other factors, and cannot generally be defined. Forexample, for an adult per day, an amount corresponding 0.1 to 1000 mg ofthe compound of the present invention can be administered or applied ina single dose or in two or more divided doses.

Another aspect of the present invention provides a method for treatingthe above-mentioned diseases, the method comprising the step ofadministering an effective amount of the compound of the presentinvention to a human or non-human mammal.

Further, the compound of the present invention has TNF-α productioninhibitory activity and IL-4 production inhibitory activity, and thus isuseful as an active ingredient in a TNF-α production inhibitor or anIL-4 production inhibitor. The form, route of administration, dosageamount and the like of a TNF-α production inhibitor or an IL-4production inhibitor comprising the compound of the present inventionare the same as those of the above-mentioned PDE4 inhibitor andpreventive or therapeutic agent.

EXAMPLES

The following Examples are given to illustrate the present invention,and are not intended to limit the scope of the invention.

Reference Example 1 Production of ethyl 2-benzoyl-4-bromo-4-pentenoate

Sodium hydride (0.26 g, 6.0 mmol) was added under ice cooling to asolution (10 ml) of ethyl benzoylacetate (1.0 ml, 5.77 mmol) in DMF,followed by stirring for 30 minutes, and then 2,3-dibromopropene (0.63ml, 5.77 mmol) was added. The resulting mixture was stirred at roomtemperature for 1.5 hours, water was added to the reaction mixture, andextraction with ethyl acetate was performed three times. The organiclayer was dried over anhydrous sodium sulfate, the solvent was distilledoff under reduced pressure, and the residue was purified by silica gelcolumn chromatography (eluent: n-hexane/ethyl acetate=4/1). The solventwas distilled off under reduced pressure, to thereby obtain 1.55 g(yield: 86%) of ethyl 2-benzoyl-4-bromo-4-pentenoate as a colorless oil.

NMRδppm(CDCl3); 8.06-8.04 (2H, m), 7.63-7.60 (1H, m), 7.52-7.49 (2H, m),5.71 (1H, d, J=1.8 Hz), 5.46 (1H, d, J=1.8 Hz), 4.81-4.79 (2H, m), 4.16(2H, q, J=7.1 Hz), 3.15-3.11 (2H, m), 1.18 (3H, t, J=7.1 Hz)

Reference Example 2 Production of ethyl2-benzoyl-5-bromo-4-oxopentanoate

N-bromosuccinimide (0.95 g, 5.3 mmol) and a drop of hydrobromic acidwere added to a solution of ethyl 2-benzoyl-4-bromo-4-pentenoate (1.5 g,4.82 mmol) in acetonitrile (16 ml) and water (4 ml), followed bystirring at room temperature for 3 hours and 40 minutes. The reactionmixture was diluted with diethyl ether, and a 5% aqueous sodiumthiosulfate solution was added to separate the mixture into layers. Theorganic layer was washed twice with a saturated aqueous sodiumhydrogencarbonate solution, washed with a saturated salt solution, anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by silica gel columnchromatography (eluent: n-hexane/ethyl acetate=4/1). The solvent wasdistilled off under reduced pressure, to thereby obtain 0.91 g (yield:58%) of ethyl 2-benzoyl-5-bromo-4-oxopentenoate as a colorless oil.

NMRδppm(CDCl3); 8.03-8.01 (2H, m), 7.63-7.59 (1H, m), 7.51-7.48 (2H, m),4.93 (1H, dd, J=6.4 Hz, 7.5 Hz), 4.15 (2H, q, J=7.1 Hz), 4.05 (2H, dd,J=13.0 Hz, 21.7 Hz), 3.43 (1H, dd, J=7.5 Hz, 18.1 Hz), 3.36 (1H, dd,J=6.4 Hz, 18.1 Hz), 1.16 (3H, t, J=7.1 Hz)

Reference Example 3 Production of4-chloromethyl-2-(3,4-diethoxyphenyl)thiazole

3,4-diethoxythiobenzamide (30.0 g, 133 mmol) was suspended in ethanol(300 ml), and 1,3-dichloroacetone (12.8 ml, 135 mmol) was added,followed by heating under reflux for 4 hours. After cooling to roomtemperature, the solvent was distilled off under reduced pressure, andthe residue was subjected to extraction with ethyl acetate. The organiclayer was washed with a saturated aqueous sodium hydrogencarbonatesolution, and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3).The solvent was distilled off under reduced pressure, and the residuewas recrystallized from an ethyl acetate/n-hexane mixed solvent, tothereby obtain 26.9 g (yield: 68%) of4-chloromethyl-2-(3,4-diethoxyphenyl)thiazole as yellow prisms.

Melting point: 81.5-82.3° C.

Reference Example 4 Production of2-(3,4-diethoxyphenyl)thiazole-4-carboxaldehyde

N-methylmorpholine-N-oxide (16.5 g, 141 mmol) was added to a solution(200 ml) of 4-chloromethyl-2-(3,4-diethoxyphenyl)thiazole (13.99 g, 47mmol) in acetonitrile, followed by heating under reflux for 1.5 hours.After cooling to room temperature, the solvent was distilled off underreduced pressure, and the residue was subjected to extraction with ethylacetate. The organic layer was washed with a saturated salt solution,and dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (eluent: ethyl acetate/n-hexane=1/2). The solventwas distilled off under reduced pressure, to thereby obtain 11.2 g(yield: 86%) of 2-(3,4-diethoxyphenyl)thiazole-4-carboxaldehyde as ayellow solid.

Melting point: 84.0-87.0° C.

Reference Example 5 Production of3-[2-(3,4-diethoxyphenyl)-thiazole-4-yl]propionic acid

Bromine (55 ml, 1.07 mol) was added dropwise under ice cooling to asolution (1.2 l) of dimethyl acetyl succinate (200 g, 1.06 mol) indiethyl ether. The resulting mixture was stirred at room temperatureovernight, and the solvent was distilled off under reduced pressure.Acetic acid (0.4 l) and concentrated hydrochloric acid (0.4 l) wereadded to the residue, and the resulting mixture was stirred at roomtemperature for 4.5 hours and further at 80° C. for 3.5 hours. Thesolvent was distilled off under reduced pressure, and3,4-diethoxythiobenzamide (215.5 g, 0.96 mol), dimethoxyethane (0.8 l)and water (0.4 l) were added to the residue, followed by stirring at 80°C. for 1 hour. After cooling to room temperature, the precipitatedcrystals were collected by filtration, washed with water, and dried at60° C. to thereby obtain 305.15 g (yield: 83%) of3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionic acid as a light brownpowder.

Melting point: 111.3-113.5° C.

Reference Example 6 Production of methyl3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionate

A solution (2.3 l) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionicacid (254.5 g) in methanol was ice-cooled, and 58 ml of thionyl chloridewas added dropwise. After completion of the addition, the resultingmixture was heated under reflux for 2 hours and cooled to roomtemperature. The solvent was distilled off under reduced pressure, andthe residue was subjected to extraction with ethyl acetate. The organiclayer was washed with a saturated aqueous sodium hydrogencarbonatesolution, and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3).The solvent was distilled off under reduced pressure, and the residuewas recrystallized from an ethyl acetate/n-hexane mixed solvent, tothereby obtain 219.35 g (yield: 68%) of methyl3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionate as a white powder.

Melting point; 58.1-58.3° C.

Reference Example 7 Production of3-[2-(3,4-diethoxyphenyl)]-thiazole-4-yl]-N-methoxy-N-methylpropionamide

1-hydroxybenzotriazole (22.91 g, 149.6 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (28.68g, 149.6 mmol), N,O-dimethylhydroxylamine hydrochloride (13.93 g, 136mmol) and triethylamine (41.7 ml, 299.2 mmol) were added to a solution(1.0 l) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionic acid (43.71g, 136 mmol) in dichloromethane, followed by stirring at roomtemperature for 4 hours. Water was added to separate the reactionmixture into layers, and the aqueous layer was further subjected toextraction with dichloromethane. The organic layer was dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent: ethyl acetate/n-hexane=1/3). The solvent wasdistilled off under reduced pressure, and the residue was recrystallizedfrom an ethyl acetate/n-hexane mixed solvent, to thereby obtain 42.4 g(yield: 68%) of3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-N-methoxy-N-methylpropionamideas colorless prisms.

Melting point: 72.0-73.0° C.

Example 1 Production of(E)-3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(2-methoxyphenyl)propenone

2-methoxyacetophenone (0.16 ml, 1.2 mmol) was added to a solution (5 ml)of 2-(3,4-diethoxyphenyl)thiazole-4-carboxaldehyde (310.5 mg, 1.12 mmol)in ethanol at room temperature. A 1M aqueous potassium hydroxidesolution (2.24 ml, 2.24 mmol) was then added dropwise at the sametemperature. After stirring at room temperature for 1 hour, water wasadded to the reaction mixture, followed by extraction withdichloromethane. The extract was dried over anhydrous sodium sulfate,and the solvent was distilled off under reduced pressure. The residuewas recrystallized from ethyl acetate/n-hexane, to thereby obtain 400 mg(yield: 94%) of(E)-3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(2-methoxyphenyl)propenoneas a yellow powder.

Melting point: 130-131° C.

Example 2 Production of(E)-3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(2-methoxyphenyl)propenone

Sodium hydride (353.3 mg, 8.83 mmol) was added to a solution (80 ml) ofdiethyl[2-(2-methoxyphenyl)-2-oxoethyl]phosphonate (2.30 g, 8.03 mmol)in THF at room temperature. After stirring at the same temperature for30 minutes, 2-(3,4-diethoxyphenyl)thiazole-4-carboxaldehyde (2.15 g,7.75 mmol) was added, and the resulting mixture was stirred at roomtemperature for 22 hours. The solvent was distilled off under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent: n-hexane/ethyl acetate=3/1 to 2/1). The solventwas distilled off under reduced pressure, and the residue wasrecrystallized from ethyl acetate/n-hexane, to thereby obtain 1.62 g(yield: 51%) of(E)-3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(2-methoxyphenyl)propenoneas yellow prisms.

Melting point: 130-131° C.

Example 3 Production of(E)-3-[2-(3,4-dimethoxyphenyl)thiazole-4-yl]-1-(3,4-diacetoxyphenyl)propenone

2-(3,4-dimethoxyphenyl)thiazole-4-carboxaldehyde (450 mg, 1.81 mmol) and3,4-diacetoxybenzoyl methylene-triphenylphosphorane (900 mg, 1.81 mmol)were suspended in THF (25 ml), and the suspension was heated underreflux for 20 hours. After cooling, the solvent was distilled off underreduced pressure, and the residue was purified by silica gel columnchromatography (eluent: dichloromethane). The solvent was distilled offunder reduced pressure, and the residue was recrystallized from ethylacetate/n-hexane, to thereby obtain 380 mg (yield: 44.9%) of(E)-3-[2-(3,4-dimethoxyphenyl)thiazole-4-yl]-1-(3,4-diacetoxyphenyl)propenoneas a yellow powder.

Melting point: 163-164° C.

Examples 4 to 34

According to the production process of Example 1, the followingcompounds of Examples 4 to 34 were produced (Table 1). Table 1 alsoshows the melting points of these compounds. TABLE 1

Melting point Examples Ra Rb Rc Rd Re Rf Rg (° C.) Salt 4 —C₂H₅ —C₂H₅—OCH₂OCH₃ —H —OCH₂OCH₃ —H —OH 140.3-143   — 5 —C₂H₅ —C₂H₅ —H —H—OCH₂OCH₃ —OCH₂OCH₃ —H 89.8-91.5 — 6 —CH₃ —CH₃ —H —OH —H —OH —H 164-168hydrochloride (degrade) 7 —CH₃ —CH₃ —H —OH —OH —H —H 162-165hydrochloride 8 —C₂H₅ —C₂H₅ —H —H —OCOCH₃ —OCOCH₃ —H 139-140 — 9 —C₂H₅—C₂H₅ —OH —H —OH —H —OH 188-189 — 10 —C₂H₅ —C₂H₅ —H —H —OH —H —H 133-134— 11 —C₂H₅ —C₂H₅ —H —OCH₃ —OCH₃ —OCH₃ —H 155-156 — 12 —C₂H₅ —C₂H₅ —H —Cl—NH₂ —Cl —H 165-168 hydrochloride 13 —C₂H₅ —C₂H₅ —H —H —OCH₃ —OCH₃ —H152-153 — 14 —C₂H₅ —C₂H₅ —H —H —H —H —H 129-130 — 15 —C₂H₅ —C₂H₅ —OH —H—H —H —H 126-127 hydrobromide 16 —C₂H₅ —C₂H₅ —H —H —H —OH —H 144.5-146  — 17 —C₂H₅ —C₂H₅ —H —H —CO₂CH₃ —H —H 150-151 — 18 —C₂H₅ —C₂H₅ —H —H —CN—H —H 164-167 — 19 —C₂H₅ —C₂H₅ —H —H —OH —CO₂H —H 195-196 — 20 —C₂H₅—C₂H₅ —H —H —OH —CO₂CH₃ —H 161.3-162.8 — 21 —C₂H₅ —C₂H₅ —H —H —Cl —H —H131-133 — 22 —CH₃ —CH₃ —H —C(CH₃)₃ —OH —C(CH₃)₃ —H 228-230 — 23 —C₂H₅—C₂H₅ —H —H —COCH₃ —H —H 128-129 — 24 —C₂H₅ —C₂H₅ —H —H —H —NO₂ —H125-126 — 25 —C₂H₅ —C₂H₅ —H —H —F —H —H 116-121 — 26 —C₂H₅ —C₂H₅ —H —H—CH₃ —H —H   124-125.5 — 27 —C₂H₅ —C₂H₅ —H —H —H —H —NO₂ 142-143 — 28—C₂H₅ —C₂H₅ —H —H —NHCOCH₃ —H —H 199.5-201.5 — 29 —C₂H₅ —C₂H₅ —H —H —Cl—Cl —H 138-139 — 30 —C₂H₅ —C₂H₅ —H —H —NH₂ —H —H 148-150 — 31 —C₂H₅—C₂H₅ —H —H —OC₂H₅ —H —H 130-135 — 32 —C₂H₅ —C₂H₅ —H —H —NO₂ —H —H125-127 33 —C₂H₅ —C₂H₅ —H —H —H —H —CO₂CH₃ 132-133 — 34 —C₂H₅ —C₂H₅ —H—H —CON(CH₃)₂ —H —H 110-112 —

Examples 35 to 36

According to the production process of Example 1, the followingcompounds of Examples 35 and 36 were produced (Table 2). Table 2 alsoshows physicochemical characteristics of these compounds. TABLE 2

Examples Ra Rb Rc Rd Re Rf Rg NMR δ ppm (CDCl₃) 35 —C₂H₅ —C₂H₅ —OCH₂OCH₃—H —OCH₂OCH₃ —H —OCH₂OCH₃ 7.58 (1 H, d, 2.0 Hz), 7.47 (1 H, dd, J = 2.0,8.4 Hz), 7.35-7.33 (3 H, m), 6.92 (1 H, J = 8.4 Hz), 6.57 (2 H, s), 5.19(2 H, s), 5.13 (4 H, s), 4.21 (2 H, q, J = 7.0 Hz), 4.13 (2 H, q, J =7.0 Hz), 3.51 (3 H, s), 3.41 (6 H, s), 1.51 (3 H, t, J = 7.0 Hz), 1.49(3 H, J = 7.0 Hz). 36 —CH₃ —CH₃ —H —H —OH —CO₂CH₃ —H 11.28 (1 H, s),8.67 (1 H, d, J = 2.2 Hz), 8.28 (1 H, dd, J = 2.4, 8.8 Hz), 8.00 (1 H,d, J = 15.0 Hz), 7.79 (1 H, d, J = 15.0 Hz), 7.61 (1 H, d, J = 2.4 Hz),7.59 (1 H, dd, J = 2.2, 8.2 Hz), 7.49 (1 H, s), 7.13 (1 H, d, J = 8.8Hz), 6.97 (1 H, d, J = 8.2 Hz), 4.03 (3 H, s), 4.02 (3 H, s), 3.97 (3 H,s)

Examples 37 to 42

According to the production process of Example 1, the followingcompounds of Examples 37 to 42 were produced (Table 3). Table 3 alsoshows physicochemical characteristics of these compounds. TABLE 3

Melting point Examples Ra Rb Rc Rd Re Rf Rg (° C.) Salt 37 —CH₃ —CH₃ —H—H —OH —H —H 174-177 — 38 —CH₃ —CH₃ —H —H —O(CH₂)₂N(C₂H₅)₂ —H —H 178-183trihydrochloride 39 —CH₃ —CH₃ —H —H —OH —CO₂H —H 227.4-228   — 40 —C₂H₅—C₂H₅ —OCH₃ —H —H —OCH₃ —H 79-82 — 41 —CH₃ —CH₃ —H —H

—H —H 165-166 — 42 —C₂H₅ —C₂H₅ —H —H

—H —H 135 (degraded) dihydrochloride

Examples 43 to 57

According to the production process of Example 1, the followingcompounds of Examples 43 to 57 were produced (Table 4). Table 4 alsoshows physicochemical characteristics of these compounds. TABLE 4

Melting point Examples Ra Rb Rh (° C.) Salt 43 —CH₃ —CH₃ -4-PYRIDYL167-168 — 44 —CH₃ —CH₃ -3-PYRIDYL 168-169 — 45 —CH₃ —CH₃ -2-PYRIDYL137-139 — 46 —CH₃ —CH₃ -2-FURYL 154-156 — 47 —CH₃ —CH₃ -2-THIENYL157-158 — 48 —CH₃ —CH₃ -3-THIENYL 178-179 — 49 —C₂H₅ —C₂H₅ -2-PYRIDYL92.2-93.8 — 50 —CH₃ —CH₃

175-177 — 51 —CH₃ —CH₃

152-153 — 52 —CH₃ —CH₃

176-177 — 53 —CH₃ —CH₃

197-199 — 54 —CH₃ —CH₃

146-147 — 55 —C₂H₅ —C₂H₅

116-117 — 56 —CH₃ —CH₃

147-149 dihydrochloride 57 —CH₃ —CH₃

222-224 (degraded) —

Example 58 Production of methyl2-[2-(3,4-diethoxyphenyl)thiazole-4-ylmethyl]-3-(3-ethoxypyridine-2-yl)-3-oxopropionate

Sodium hydride (239 mg, 6.0 mmol) and a drop of methanol were added to asolution (10 ml) of methyl3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionate (1.0 g, 3.0 mmol) andmethyl 3-ethoxypyridine-2-carboxylate (702 mg, 3.9 mmol) indimethoxyethane, followed by heating under reflux for 2 hours. Aftercooling to room temperature, a saturated aqueous ammonium chloridesolution was added to the reaction mixture, and the resulting mixturewas subjected to extraction with ethyl acetate. The organic layer waswashed with a saturated salt solution, and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by silica gel column chromatography(eluent: ethyl acetate/n-hexane=2/3). The solvent was distilled offunder reduced pressure, to thereby obtain 740 mg (yield: 51%) of methyl2-[2-(3,4-diethoxyphenyl)thiazole-4-ylmethyl]-3-(3-ethoxypyridine-2-yl)-3-oxopropionateas a yellow oil.

HNMRδppm(CDCl3); 8.22 (1H, dd, J=1.3 Hz, 4.3 Hz), 7.44 (1H, d, J=2.1Hz), 7.4-7.2 (3H, m), 6.92 (1H, s), 6.85 (1H, d, J=8.4 Hz), 5.29 (1H, t,J=7.4 Hz), 4.2-4.0 (6H, m), 3.65 (3H, s), 3.6-3.4 (2H, m), 1.5-1.4 (9H,m)

Example 59 Production of ethyl2-[2-(3,4-diethoxyphenyl)thiazole-4-ylmethyl]-3-oxo-3-phenylpropionate

3,4-diethoxythiobenzamide (0.63 g, 2.8 mmol) was added to a solution (20ml) of ethyl 2-benzoyl-5-bromo-4-oxopentanoate (0.90 g, 2.8 mmol) inethanol, followed by heating under reflux for 1.5 hours. After coolingto room temperature, the solvent was distilled off under reducedpressure, and the residue was subjected to extraction with ethylacetate. The organic layer was washed with a saturated aqueous sodiumhydrogencarbonate solution and a saturated salt solution, and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, to thereby obtain 1.43 g (yield: 65%) of ethyl2-[2-(3,4-diethoxyphenyl)thiazole-4-ylmethyl]-3-oxo-3-phenylpropionateas a yellow oil.

NMRδppm(CDCl3); 8.06-8.05 (2H, m), 7.58-7.55 (1H, m), 7.47-7.44 (2H, m),7.40 (1H, d, J=2.0 Hz), 7.36 (1H, dd, J=2.0 Hz, 8.4 Hz), 6.90 (1H, s),6.86 (1H, d, J=8.4 Hz), 5.06-5.03 (1H, m), 4.17-4.07 (6H, m), 3.50-3.49(2H, m), 1.47 (6H, t, J=7.0 Hz), 1.15 (3H, t, J=7.2 Hz)

Examples 60 to 66

According to the production process of Example 58, the followingcompounds of Examples 60 to 66 were produced (Table 5). Table 5 alsoshows physicochemical characteristics of these compounds. TABLE 5

Examples Ra Rb Rc Rd Re Rf Rg Ri NMR δ ppm (CDCl₃) 60 —C₂H₅ —C₂H₅ —H —H—Cl —H —OCH₃ —CH₃ 7.71 (1 H, d, J = 8.3 Hz), 7.41 (1 H, d, J = 2.0 Hz),7.35 (1 H, dd, J = 2.0 Hz, 8.3 Hz), 6.98 (1 H, dd, J = 1.8 Hz, 8.4 Hz),6.92 (1 H, d, J = 1.8 Hz), 6.9-6.8 (2 H, m), 4.95 (1 H, dd, J = 6.5 Hz,7.8 Hz), 4.2-4.0 (4 H, m), 3.85 (3 H, s), 3.69 (3 H, s), 3.6-3.3 (2 H,m), 1.5-1.4 (6 H, m) 61 —C₂H₅ —C₂H₅ —H —H —H —Cl —OCH₃ —CH₃ 7.5-7.3 (4H, m), 7.04 (1 H, t, J = 7.9 Hz), 6.89 (1 H, s), 6.85 (1 H, d, J = 8.4Hz), 5.09 (1 H, dd, J = 6.6 Hz, 8.0 Hz), 4.2-4.0 (4 H, m), 3.84 (3 H,s), 3.70 (3 H, s), 3.5-3.4 (2 H, m), 1.5-1.4 (6 H, m) 62 —C₂H₅ —C₂H₅ —H—H —H —H —OC₂H₅ —C₂H₅ 7.68 (1 H, dd, J = 1.8 Hz, 7.7 Hz), 7.5-7.3 (3 H,m), 7.0-6.8 (4 H, m), 5.14 (1 H, t, J = 7.3 Hz), 4.2-4.0 (8 H, m),3.6-3.3 (2 H, m), 1.5-1.3 (9 H, m), 1.13 (3 H, t, J = 7.1 Hz) 63 —C₂H₅—C₂H₅ —H —H —H —H —N(CH₃)₂ —C(CH₃)₃ 7.49 (1 H, d, J = 1.9 Hz), 7.43-7.2(3 H, m), 7.0-6.8 (4 H, m), 5.28 (1 H, t, J = 7.1 Hz), 4.2-4.1 (4 H, m),3.36 (2 H, dd, J = 2.2 Hz, 7.1 Hz), 2.69 (6 H, s), 1.5-1.4 (6 H, m),1.27 (9 H, s) 64 —C₂H₅ —C₂H₅ —H —H —H —H —OCH₂OCH₃ —CH₃ 7.69 (1 H, dd, J= 7.8 Hz), 7.5-7.3 (3 H, m), 7.19 (1 H, d, J = 8.4 Hz), 7.1-7.0 (1 H,m), 6.88 (1 H, s), 6.85 (1 H, d, J = 8.4 Hz), 5.22 (2 H, s), 5.1-5.0 (1H, m), 4.2-4.0 (4 H, m), 3.68 (3 H, s), 3.6-3.3 (5 H, m), 1.5-1.4 (6 H,m) 65 —C₂H₅ —C₂H₅ —H —H —H —H —OC₆H₅ —CH₃ 7.80 (1 H, dd, J = 1.8 Hz, 7.8Hz), 7.4-7.2 (5 H, m), 7.2-6.9 (4 H, m), 6.9-6.8 (3 H, m), 5.13 (1 H,dd, J = 6.2 Hz, 8.3 Hz), 4.2-4.0 (4 H, m), 3.7-3.3 (5 H, m), 1.5-1.4 (6H, m) 66 —C₂H₅ —C₂H₅ —H —H —H —H —OCH₃ —CH₃ 7.74 (1 H, dd, J = 1.8 Hz,7.7 Hz), 7.5-7.4 (2 H, m), 7.36 (1 H, dd, J = 2.1 Hz, 8.3 Hz), 7.1-6.8(4 H, m), 4.97 (1 H, t, J = 7.2 Hz), 4.2-4.0 (4 H, m), 3.85 (3 H, s),3.69 (3 H, s), 3.6-3.3 (2 H, m), 1.5-1.4 (6 H, m)

Examples 67 to 71

According to the production process of Example 58, the followingcompounds of Examples 67 to 71 were produced (Table 6). Table 6 alsoshows physicochemical characteristics of these compounds. TABLE 6

Examples Ra Rb Rc Rd Re Rf Rg Ri MS(M + 1) 67 —C₂H₅ —C₂H₅ —H —H —H —H—CN —CH₃ 465 68 —C₂H₅ —C₂H₅ —H —H —H —H —OC₂H₅ —CH₃ 484 69 —C₂H₅ —C₂H₅—H —H —H —H —Cl —CH₃ 474 70 —C₂H₅ —C₂H₅ —H —Cl —H —H —OCH₃ —CH₃ 504 71—C₂H₅ —C₂H₅ —H —H —H —H —CH₃ —CH₃ 454

Examples 72 to 75

According to the production process of Example 58, the followingcompounds of Examples 72 to 75 were produced (Table 7). Table 7 alsoshows physicochemical characteristics of these compounds. TABLE 7

Examples Ra Rb Rh Rj MS(M + 1) 72 —C₂H₅ —C₂H₅ -2-PYRIDYL —CH₃ 441 73—C₂H₅ —C₂H₅ -3-PYRIDYL —CH₃ 441 74 —C₂H₅ —C₂H₅

—CH₃ 443 75 —C₂H₅ —C₂H₅

—CH₃ 455

Examples 76 to 82

According to the production process of Example 58, the followingcompounds of Examples 76 to 82 were produced (Table 8). Table 8 alsoshows physicochemical characteristics of these compound. TABLE 8

Examples Ra Rb Rh Rj NMR δ ppm (CDCl₃) 76 —C₂H₅ —C₂H₅ -2-FURYL —CH₃ 7.60(1 H, d, J = 1.6 Hz), 7.43 (1 H, d, J = 2.0 Hz), 7.4-7.3 (2 H, m), 6.89(1 H, s), 6.86 (1 H, d, J = 8.4 Hz), 6.52 (1 H, dd, J = 1.7 Hz, 3.6 Hz),4.81 (1 H, t, J = 7.4 Hz), 4.2-4.0 (4 H, m), 3.71 (3 H, s), 3.48 (2 H,d, J = 7.4 Hz) 1.5-1.4 (6 H, m) 77 —C₂H₅ —C₂H₅ -4-PYRIDYL —CH₃ 8.8-8.7(2 H, m), 7.9-7.8 (2 H, m), 7.32 (1 H, d, J = 1.9 Hz), 7.3-7.2 (1 H, m),6.90 (1 H, s), 6.83 (1 H, d, J = 8.3 Hz), 5.05 (1 H, dd, J = 6.6 Hz, 8.0Hz), 4.2-4.0 (4 H, m), 3.70 (3 H, s), 3.6-3.4 (2 H, m), 1.5-1.4 (6 H, m)78 —C₂H₅ —C₂H₅

—CH₃ 8.23 (1 H, dd, J = 1.2 Hz, 4.4 Hz), 7.5-7.3 (4 H, m), 6.92 (1 H,s), 6.85 (1 H, d, J = 8.4 Hz), 5.30 (1 H, dd, J = 6.9 Hz, 7.8 Hz),4.2-4.0 (4 H, m), 3.89 (3 H, s), 3.65 (3 H, s), 3.6-3.4 (2 H, m),1.5-1.4 (6 H, m) 79 —C₂H₅ —C₂H₅

—CH₃ 8.21 (1 H, dd, J = 1.7 Hz, 4.0 Hz), 7.45 (1 H, d, J = 1.9 Hz),7.4-7.2 (3 H, m), 6.92 (1 H, s), 6.85 (1 H, d, J = 8.4 Hz), 5.28 (1 H,t, J = 7.3 Hz), 4.6-4.5 (1 H, m), 4.2-4.0 (4 H, m), 3.65 (3 H, s),3.6-3.4 (2 H, m), 1.5-1.4 (6 H, m), 1.37 (3 H, s), 1.35 (3 H, s) 80—C₂H₅ —C₂H₅

—CH₃ 7.89 (1 H, d, J = 8.1 Hz), 7.5-7.3 (4 H, m), 7.19 (1 H, dd, J = 2.1Hz, 8.4 Hz), 6.95 (1 H, s), 6.74 (1 H, d, J = 8.4 Hz), 5.59 (1 H, dd, J= 6.0 Hz, 8.9 Hz), 4.2-3.9 (7 H, m), 3.71 (3 H, s), 3.7-3.4 (2 H, m),1.5-1.3 (6 H, m) 81 —C₂H₅ —C₂H₅

—CH₃ 9.27 (1 H, d, J = 1.5 Hz), 8.73 (1 H, d, J = 2.5 Hz), 8.62 (1 H,dd, J = 1.5 Hz, 2.4 Hz), 7.31 (1 H, d, J = 2.1 Hz), 7.3-7.2 (1 H, m),6.91 (1 H, s), 6.81 (1 H, d, J = 8.4 Hz), 5.38 (1 H, dd, J = 5.8 Hz, 8.9Hz), 4.2-4.0 (4 H, m), 3.67 (3 H, s), 3.6-3.4 (2 H, m), 1.5-1.4 (6 H, m)82 —C₂H₅ —C₂H₅

—CH₃ 8.27 (1 H, d, J = 8.5 Hz), 8.2-8.1 (2 H, m), 7.9-7.6 (3 H, m), 7.37(1 H, d, J = 2.0 Hz), 7.29 (1 H, dd, J = 2.1 Hz, 8.4 Hz), 6.93 (1 H, s),6.80 (1 H, d, J = 8.3 Hz), 5.60 (1 H, dd, J = 6.3 Hz, 8.3 Hz), 4.2-4.0(4 H, m), 3.7-3.5 (5 H, m), 1.5-1.3 (6 H, m)

Examples 83 to 86

According to the production process of Example 58, the followingcompounds of Examples 83 to 86 were produced (Table 9). Table 9 alsoshows physicochemical characteristics of these compounds. TABLE 9

Examples Ra Rb Rh Rj NMR δ ppm (CDCl₃) 83 —C₂H₅ —C₂H₅

—CH₃ 8.5-8.4 (1 H, m), 7.56 (1 H, d, J = 7.8 Hz), 7.41 (1 H, d, J = 2.0Hz), 7.4-7.2 (2 H, m), 6.91 (1 H, s), 6.84 (1 H, d, J = 8.4 Hz), 5.35 (1H, dd, J = 6.6 Hz, 8.1 Hz), 4.2-4.0 (4 H, m), 3.66 (3 H, s), 3.6-3.3 (2H, m), 2.56 (3 H, s), 1.5-1.4 (6 H, m) 84 —C₂H₅ —C₂H₅

—CH₃ 8.3-8.2 (1 H, m), 7.5-7.3 (9 H, m), 6.91 (1 H, s), 6.82 (1 H, d, J= 8.4 Hz), 5.32 (1 H, t, J = 7.4 Hz), 5.17 (2 H, s), 4.2-4.0 (4 H, m),3.65 (3 H, s), 3.6-3.4 (2 H, m), 1.5-1.4 (6 H, m) 85 —C₂H₅ —C₂H₅

—CH₃ 9.02 (1 H, s), 8.51 (1 H, d, J = 5.0 Hz), 7.4-7.3 (2 H, m), 7.15 (1H, d, J = 5.0 Hz), 6.91 (1 H, s), 6.85 (1 H, d, J = 8.3 Hz), 5.1-5.0 (1H, m), 4.2-4.0 (4 H, m), 3.70 (3 H, s), 3.6-3.4 (2 H, m), 2.43 (3 H, s),1.5-1.4 (6 H, m) 86 —C₂H₅ —C₂H₅

—C(CH₃)₃ 7.48 (1 H, d, J = 2.1 Hz), 7.40 (1 H, dd, J = 2.1 Hz, 8.3 Hz),7.14 (1 H, dd, J = 1.7 Hz, 4.2 Hz), 6.9-6.8 (3 H, m), 6.11 (1 H, dd, J =2.5 Hz, 4.2 Hz), 4.64 (1 H, t, J = 7.3 Hz), 4.2-4.1 (4 H, m), 3.92 (3 H,s), 3.41 (2 H, d, J = 7.4 Hz), 1.5-1.4 (6 H, m), 1.37 (9 H, s)

Example 87 Production of3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(3-ethoxypyridine-2-yl)-1-propanone

Methyl2-[2-(3,4-diethoxyphenyl)thiazole-4-ylmethyl]-3-(3-ethoxypyridine-2-yl)-3-oxopropionate(730 mg, 1.5 mmol) was added to a mixture of acetic acid (4.5 ml) andhydrochloric acid (1.5 ml), followed by heating with stirring at 100 to110° C. for 6 hours. After cooling to room temperature, the reactionmixture was added to an aqueous solution of sodium carbonate (5.3 g,0.05 mol), and the resulting mixture was subjected to extraction withethyl acetate. The organic layer was washed with a saturated saltsolution, and dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: ethyl acetate/n-hexane=3/4).The solvent was distilled off under reduced pressure, and the residuewas recrystallized from ethanol, to thereby obtain 475 g (yield: 74%) of3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(3-ethoxypyridine-2-yl)-1-propenoneas colorless needles.

Melting point: 66.7-68.2° C.

Example 88 Production of3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(3-methoxypyridine-2-yl)-1-propanone

Triethylamine (0.19 ml, 1.36 mmol) and sulfur trioxide pyridine complex(0.11 g, 0.68 mmol) were added to a solution (5 ml) of3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(3-methoxypyridine-2-yl)-1-propane-1-ol(0.14 g, 0.34 mmol) in DMSO, and the resulting mixture was stirred atroom temperature for 1 hour. Water was added to the reaction mixture,and extraction with diethyl ether was carried out three times. Theorganic layer was dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bypreparative thin-layer silica gel column chromatography (eluent:dichloromethane/methanol=10/1). The solvent was distilled off underreduced pressure, to give 120 mg (yield: 86%) of3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(3-methoxypyridine-2-yl)-1-propanoneas a colorless oil. The oil was recrystallized from hydrous ethanol, tothereby obtain3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(3-methoxypyridine-2-yl)-1-propanoneas yellow needles.

Melting point: 79.2-79.7° C.

Example 89 Production of3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(2-methoxyphenyl)-1-propanone

(E)-3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(2-methoxyphenyl)propenone(1.62 g, 4.0 mmol) was dissolved in a mixed solvent of ethyl acetate (40ml), methanol (10 ml) and DMF (10 ml), and 400 mg of 10%palladium/carbon was added to perform catalytic reduction in a hydrogenatmosphere at room temperature and atmospheric pressure for 4 hours. Thereaction mixture was filtered, the solvent was distilled off underreduced pressure, and the residue was purified by silica gel columnchromatography (eluent: ethyl acetate/n-hexane=3/2 to 1/1). The solventwas distilled off under reduced pressure, and the residue wasrecrystallized from diethyl ether, to thereby obtain 750 mg (yield: 46%)of3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(2-methoxyphenyl)-1-propanoneas colorless prisms.

Melting point: 68.9-69.3° C.

Example 90 Production of3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-thiazole-2-yl-1-propanone

A solution (2 ml) of thiazole (129 mg, 1.5 mmol) in THF was cooled to−70° C., and n-butyllithium (a 2.44M hexane solution) (0.62 ml, 1.5mmol) was added, and the resulting mixture was stirred at −70° C. for 30minutes. A solution (4 ml) of3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-N-methoxy-N-methylpropionamide(500 mg, 1.4 mmol) in THF was added to the reaction mixture, followed bystirring at −70° C. for 3 hours. After heating to room temperature, asaturated aqueous ammonium chloride solution was added to the reactionmixture, followed by extraction with ethyl acetate. The organic layerwas washed with a saturated salt solution, and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by silica gel column chromatography(eluent: ethyl acetate/n-hexane=1/5). The solvent was distilled offunder reduced pressure, and the residue was recrystallized from ethanol,to thereby obtain 350 mg (yield: 66%) of3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-thiazole-2-yl-1-propanone ascolorless needles.

Melting point: 93.1-94.4° C.

Examples 91 to 108

According to the production process of Example 87, the followingcompounds of Examples 91 to 108 were produced (Table 10). Table 10 alsoshows physicochemical characteristics of these compounds. TABLE 10

Melting point Examples Ra Rb Rc Rd Re Rf Rg (° C.) Salt 91 —C₂H₅ —C₂H₅—H —H —H —H —H 113.3-113.6 — 92 —C₂H₅ —C₂H₅ —H —H —OH —OH —H 153.2-153.8hydrochloride 93 —CH₃ —CH₃ —H —H —OC₂H₅ —OC₂H₅ —H 141.3-142.4 — 94 —CH₃—CH₃ —H —H —OCOCH₃ —OCOCH₃ —H   128-128.5 — 95 —C₂H₅ —C₂H₅ —OCH₃ —H —H—OCH₃ —H 97.8-98.5 — 96 —C₂H₅ —C₂H₅ —H —H —H —H —OCH₃ 68.9-69.3 — 97—C₂H₅ —C₂H₅ —H —H —H —H —OC₆H₅ 118.2-119   — 98 —C₂H₅ —C₂H₅ —OH —H —H —H—H 113.7-114.9 — 99 —C₂H₅ —C₂H₅ —CF₃ —H —H —H —H 91.7-93   — 100 —C₂H₅—C₂H₅ —OC₂H₅ —H —H —H —H 84.3-86.1 — 101 —C₂H₅ —C₂H₅ —F —H —H —H —H82.5-83.5 — 102 —C₂H₅ —C₂H₅ —CN —H —H —H —H 113.7-114.8 — 103 —C₂H₅—C₂H₅ —Br —H —H —H —H 66.1-67.9 — 104 —C₂H₅ —C₂H₅ —Cl —H —H —H —H64.4-65.1 — 105 —C₂H₅ —C₂H₅ —H —H —H —H —CO₂CH₃ 91.7-92.9 — 106 —C₂H₅—C₂H₅ —OCH₃ —H —Cl —H —H 102.8-104.2 — 107 —C₂H₅ —C₂H₅ —CH₃ —H —H —H —H107.1-107.4 — 108 —C₂H₅ —C₂H₅ —OCH₃ —H —H —Cl —H 90.2-92   —

Examples 109 to 114

According to the production process of Example 87, the followingcompounds of Examples 109 to 114 were produced (Table 11). Table 11 alsoshows physicochemical characteristics of these compounds. TABLE 11

Examples Ra Rb Rc Rd Re Rf Rg NMR δ ppm (CDCl₃) 109 —C₂H₅ —C₂H₅ —OCH₃—Cl —H —H —H 7.6-7.3 (4 H, m), 7.10 (1 H, t, J = 7.8 Hz), 6.9-6.8 (2H,m), 4.2-4.0 (4 H, m), 3.87 (3 H, s), 3.46 (2 H, t, J = 7.1 Hz), 3.21 (2H, t, J = 7.1 Hz), 1.5-1.4 (6 H, m) 110 —C₂H₅ —C₂H₅ —N(CH₃)₂ —H —H —H —H7.49 (1 H, d, J = 2.0 Hz), 7.43-7.3 (3 H, m), 7.0-6.8 (4 H, m), 4.2-4.1(4 H, m), 3.48 (2 H, t, J = 7.3 Hz), 3.18 (2 H, t, J = 7.3 Hz), 2.73 (6H, s), 1.5-1.4 (6 H, m) 111 —C₂H₅ —C₂H₅ —H —H —H —H —CON(CH₃)₂ 7.88 (1H, d, J = 7.4 Hz), 7.6-7.3 (4 H, m), 7.3-7.2 (1 H, m), 6.9-6.8 (2 H, m),4.2-4.1 (4 H, m), 3.45 (2 H, t, J = 7.3 Hz), 3.20 (2 H, t, J = 7.2 Hz),3.14 (3 H, s), 2.76 (3 H, s), 1.5-1.4 (6 H,m) 112 —C₂H₅ —C₂H₅ —H —H —H—H —CO₂H 10.08 (1 H, br), 7.87 (1 H, d, J = 7.1 Hz), 7.7-7.3 (5 H, m),6.92 (1 H, s), 6.89 (1 H, d, J = 8.3 Hz), 4.2-4.0 (4 H, m), 3.6-3.4 (1H, m), 3.1-3.0 (1 H, m), 2.6-2.2 (2 H, m), 1.5-1.4 (6 H, m) 113 —C₂H₅—C₂H₅ —H —H —H —H —C₆H₅ 7.5-7.3 (11 H, m), 6.87 (1 H, d, J = 8.4 Hz),6.63 (1 H, s), 4.2-4.0 (4 H, m), 3.0-2.9 (2 H, m), 2.8-2.7 (2 H, m),1.5-1.4 (6 H, m) 114 —C₂H₅ —C₂H₅ —OCH₂OCH₃ —H —H —H —H 7.69 (1 H, dd, J= 7.8 Hz), 7.5-7.3 (3 H, m), 7.19 (1H, d, J = 8.4 Hz), 7.1-7.0 (1 H, m),6.88 (1 H, s), 6.85 (1H, d, J = 8.4 Hz), 5.22 (2 H, s), 5.1-5.0 (1 H,m), 4.2-4.0 (4 H, m), 3.68 (3 H, s), 3.6-3.3 (5 H, m), 1.5-1.4 (6 H, m)

Examples 115 to 147

According to the production process of Example 87, the followingcompounds of Examples 115 to 147 were produced (Table 12). Table 12 alsoshows physicochemical characteristics of these compounds. TABLE 12

Examples Ra Rb Rc Rd Re Rf Rg MS(M + 1) 115 —C₂H₅ —C₂H₅ —Cl —H —Cl—SO₂NH₂ —H 529 116 —C₂H₅ —C₂H₅ —OCH₃ —H —H —SO₂NH₂ —H 491 117 —C₂H₅—C₂H₅ —H —H —CN —H —H 407 118 —C₂H₅ —C₂H₅ —H —OCH₃ —H —OCH₃ —H 442 119—C₂H₅ —C₂H₅ —H —H —H —CH₃ —H 396 120 —C₂H₅ —C₂H₅ —H —H —CH₃ —H —H 396121 —C₂H₅ —C₂H₅ —H —H —N(CH₃)₂ —H —H 425 122 —C₂H₅ —C₂H₅ —H —H —H—N(CH₃)₂ —H 425 123 —C₂H₅ —C₂H₅ —H —H —H —Br —H 460 124 —C₂H₅ —C₂H₅ —H—H —F —H —H 400 125 —C₂H₅ —C₂H₅ —H —H —OCH₃ —CN —H 437 126 —C₂H₅ —C₂H₅—H —H —CH₃ —OCH₃ —H 426 127 —C₂H₅ —C₂H₅ —H —H —H —H —OCF₃ 466 128 —C₂H₅—C₂H₅ —H —H —H —Cl —H 416 129 —C₂H₅ —C₂H₅ —H —H —Cl —H —H 416 130 —C₂H₅—C₂H₅ —H —H —OCH₃ —OCH₃ —H 442 131 —C₂H₅ —C₂H₅ —H —H —OCH₃ —H —H 412 132—C₂H₅ —C₂H₅ —H —H —H —CF₃ —H 450 133 —C₂H₅ —C₂H₅ —H —H —H —Cl —Cl 450134 —C₂H₅ —C₂H₅ —H —H —H —H —SCH₃ 428 135 —C₂H₅ —C₂H₅ —H —H —OC₄H₉ —H —H454 136 —C₂H₅ —C₂H₅ —H —H —H —F —H 400 137 —C₂H₅ —C₂H₅ —H —Cl —H —H —Cl450 138 —C₂H₅ —C₂H₅ —H —H —H —OCH₃ —H 412 139 —C₂H₅ —C₂H₅ —H —H —C₆H₅ —H—H 458 140 —C₂H₅ —C₂H₅ —H —H —H —OC₂H₅ —H 426 141 —C₂H₅ —C₂H₅ —H —H—OC₂H₅ —H —H 426 142 —C₂H₅ —C₂H₅ —H —H —OCH₂C₆H₅ —H —H 488 143 —C₂H₅—C₂H₅ —H —H —H —OCF₃ —H 466 144 —C₂H₅ —C₂H₅ —H —H —CF₃ —H —H 450 145—C₂H₅ —C₂H₅ —H —H —C₄H₉ —H —H 438 146 —C₂H₅ —C₂H₅ —H —H —H —H —OCH₂C₆H₅488 147 —C₂H₅ —C₂H₅ —H —H —OH —H —H 398

Examples 148 to 152

According to the production process of Example 87, the followingcompounds of Examples 148 to 152 were produced (Table 13). Table 13 alsoshows physicochemical characteristics of these compounds. TABLE 13

Examples Ra Rb Rc Rd Re Rf Rg MS(M + 1) 148 —C₂H₅ —C₂H₅ —H —H

—H —H 448 149 —C₂H₅ —C₂H₅ —H —H

—H —H 449 150 —C₂H₅ —C₂H₅ —H —H

—H —H 448 151 —C₂H₅ —C₂H₅ —H —H

—H —H 449 152 —C₂H₅ —C₂H₅ —H —H

—H —H 467

Examples 153 to 157

According to the production process of Example 87, the followingcompounds of Examples 153 to 157 were produced (Table 14). Table 14 alsoshows physicochemical characteristics of these compounds. TABLE 14

Examples Ra Rb Rh Melting point(° C.) 153 —C₂H₅ —C₂H₅ -2-PYRIDYL92.9-93   154 —C₂H₅ —C₂H₅ -2-FURYL 110.8-112.5 155 —C₂H₅ —C₂H₅-2-THIENYL 106.5-107.4 156 —C₂H₅ —C₂H₅ -4-PYRIDYL 90.6-91.1 157 —C₂H₅—C₂H₅ -3-PYRIDYL 107.5-108.0

Examples 158 to 167

According to the production process of Example 87, the followingcompounds of Examples 158 to 167 were produced (Table 15). Table 15 alsoshows physicochemical characteristics of these compounds. TABLE 15

Melting point Examples Ra Rb Rh (° C.) 158 —C₂H₅ —C₂H₅

59.5-60.5 159 —C₂H₅ —C₂H₅

118.7-119.6 160 —C₂H₅ —C₂H₅

109.1-110.5 161 —C₂H₅ —C₂H₅

81.7-83.1 162 —C₂H₅ —C₂H₅

87.0-87.6 163 —C₂H₅ —C₂H₅

92.1-93.1 164 —C₂H₅ —C₂H₅

117.9-119.2 165 —C₂H₅ —C₂H₅

80.3-81.9 166 —C₂H₅ —C₂H₅

107.7-108.5 167 —C₂H₅ —C₂H₅

92.8-94.2

Example 168

According to the production process of Example 87, the followingcompound of Example 168 was produced (Table 16). Table 16 also showsphysicochemical characteristics of the compound. TABLE 16

Example Ra Rb Rh NMR δ ppm (DMSO-d6) Salt 168 —C₂H₅ —C₂H₅

8.31-8.29 (1 H, m), 8.00 (1 H, d, J = 8.7 Hz), 7.8-7.7 (1 H, m), 7.53 (1H, d, J = 2.1 Hz), 7.44 (1 H, dd, J = 2.1 Hz, 8.4 Hz), 7.36 (1 H, s),7.03 (1 H, d, J = 8.5 Hz), 4.9-4.7 (1 H, m), 4.1-4.0 (4 H, m), 3.50 (2H, t, J = 7.2 Hz), 3.11 (2 H, t, J = 7.2 Hz), 1.4-1.2 (12 H,m)hydrochloride

Examples 169 to 178

According to the production process of Example 87, the followingcompounds of Examples 169 to 178 were produced (Table 17). Table 17 alsoshows physicochemical characteristics of these compounds. TABLE 17

Ex- amples Ra Rb Rh MS(M + 1) 169 —C₂H₅ —C₂H₅

451 170 —C₂H₅ —C₂H₅

451 171 —C₂H₅ —C₂H₅

422 172 —C₂H₅ —C₂H₅

386 173 —C₂H₅ —C₂H₅

397 174 —C₂H₅ —C₂H₅

418 175 —C₂H₅ —C₂H₅

386 176 —C₂H₅ —C₂H₅

413 177 —C₂H₅ —C₂H₅

432 178 —C₂H₅ —C₂H₅

387

Examples 179 to 185

According to the production process of Example 87, the followingcompounds Examples 179 to 185 were produced (Table 18). Table 18 alsoshows physicochemical characteristics of these compounds. TABLE 18

Examples Ra Rb Rh MS(M + 1) 179 —C₂H₅ —C₂H₅

438 180 —C₂H₅ —C₂H₅

418 181 —C₂H₅ —C₂H₅

444 182 —C₂H₅ —C₂H₅

432 183 —C₂H₅ —C₂H₅

426 184 —C₂H₅ —C₂H₅

434 185 —C₂H₅ —C₂H₅

433

Example 186 Production of3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(2-methoxyphenyl)-1-propanol

Sodium borohydride (20 mg, 0.53 mmol) was added to a mixed solution of3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(2-methoxyphenyl)-1-propanone(458 mg, 1.11 mmol) in THF (10 ml) and methanol (10 ml) at roomtemperature, and the resulting mixture was stirred at the sametemperature for 1 hour. A saturated aqueous ammonium chloride solutionwas added to the reaction mixture, followed by extraction with ethylacetate. The organic layer was dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified by silica gel column chromatography (eluent: ethylacetate/n-hexane=2/1). The solvent was distilled off under reducedpressure, and the residue was recrystallized from a diethylether/n-hexane mixed solvent, to thereby obtain 336 mg (yield: 73%) of3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(2-methoxyphenyl)-1-propanolas a white powder.

Melting point: 78.2-79° C.

Example 187 Production of3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(3-methoxypyridine-2-yl)-1-propanoldihydrochloride

According to the production process of Example 186,3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(3-methoxypyridine-2-yl)-1-propanoldihydrochloride was produced.

Melting point: 161.0-161.5° C.

Example 188 Production of3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(3-methoxypyridine-2-yl)-1-propanol

A solution of 2-bromo-3-methoxypyridine (1.65 g, 8.78 mmol) in THF wascooled to −78° C., and 5.23 ml (8.16 mmol) of a 1.57 N solution ofn-butyllithium in n-hexane was added dropwise. The resulting mixture wasstirred at the same temperature for 45 minutes, and a solution (15 ml)of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionaldehyde (1.34 g, 4.39mmol) in THF was added dropwise. After stirring at the same temperaturefor 30 minutes, the temperature of the mixture was raised to −30° C.over a period of 30 minutes. A saturated aqueous ammonium chloridesolution was added to the reaction mixture, followed by extraction withethyl acetate. The organic layer was washed with a saturated saltsolution, and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1).The solvent was distilled off under reduced pressure, and the residuewas purified by preparative thin-layer silica gel column chromatography(eluent: ethyl acetate/n-hexane=1/2). The solvent was distilled offunder reduced pressure, to thereby obtain 470 mg (yield: 26%) of3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(3-methoxypyridine-2-yl)-1-propanolas a yellow oil.

Examples 189 to 208

According to the production process of Example 186, the followingcompounds of Examples 189 to 208 were produced (Table 19). Table 19 alsoshows physicochemical characteristics of these compounds. TABLE 19

Examples Ra Rb Rc Rd Re Rf Rg MS(M + 1) 189 —C₂H₅ —C₂H₅ —H —H —H —H —H384 190 —C₂H₅ —C₂H₅ —H —H —CN —H —H 409 191 —C₂H₅ —C₂H₅ —H —OCH₃ —H—OCH₃ —H 444 192 —C₂H₅ —C₂H₅ —H —H —H —CH₃ —H 398 193 —C₂H₅ —C₂H₅ —H —H—CH₃ —H —H 398 194 —C₂H₅ —C₂H₅ —H —H —N(CH₃)₂ —H —H 426(M+) 195 —C₂H₅—C₂H₅ —H —H —H —N(CH₃)₂ —H 427 196 —C₂H₅ —C₂H₅ —H —H —H —H —Br 462 197—C₂H₅ —C₂H₅ —H —H —H —H —OC₂H₅ 428 198 —C₂H₅ —C₂H₅ —H —H —H —Br —H 462199 —C₂H₅ —C₂H₅ —H —H —F —H —H 402 200 —C₂H₅ —C₂H₅ —H —H —OCH₃ —CN —H439 201 —C₂H₅ —C₂H₅ —H —H —CH₃ —OCH₃ —H 428 202 —C₂H₅ —C₂H₅ —H —H —H —H—OCF₃ 468 203 —C₂H₅ —C₂H₅ —H —H —H —H —OCH₃ 414 204 —C₂H₅ —C₂H₅ —H —H—Cl —H —H 418 205 —C₂H₅ —C₂H₅ —H —H —H —H —Cl 418 206 —C₂H₅ —C₂H₅ —H —Cl—H —H —OCH₃ 448 207 —C₂H₅ —C₂H₅ —H —H —H —CF₃ —H 452 208 —C₂H₅ —C₂H₅ —H—OCH₃ —H —H —OCH₃ 444

Examples 209 to 225

According to the production process of Example 186, the followingcompounds of Examples 209 to 225 were produced (Table 20). Table 20 alsoshows physicochemical characteristics of these compounds. TABLE 20

Examples Ra Rb Rc Rd Re Rf Rg MS(M + 1) 209 —C₂H₅ —C₂H₅ —H —H —H —Cl —Cl452 210 —C₂H₅ —C₂H₅ —H —H —H —H —SCH₃ 430 211 —C₂H₅ —C₂H₅ —H —H —H —F —H402 212 —C₂H₅ —C₂H₅ —H —Cl —H —H —Cl 452 213 —C₂H₅ —C₂H₅ —H —H —H —OCH₃—H 414 214 —C₂H₅ —C₂H₅ —H —H —C₆H₅ —H —H 460 215 —C₂H₅ —C₂H₅ —H —H —H—OC₂H₅ —H 428 216 —C₂H₅ —C₂H₅ —H —H —H —H —F 402 217 —C₂H₅ —C₂H₅ —H —H—H —OCF₃ —H 468 218 —C₂H₅ —C₂H₅ —H —H —CF₃ —H —H 452 219 —C₂H₅ —C₂H₅ —H—H —H —H —CF₃ 452 220 —C₂H₅ —C₂H₅ —H —H —C₄H₉ —H —H 440 221 —C₂H₅ —C₂H₅—H —H —H —H —CN 409 222 —C₂H₅ —C₂H₅ —H —H —OCH₃ —OCH₃ —H 444 223 —C₂H₅—C₂H₅ —H —H —OCH₃ —H —H 414 224 —C₂H₅ —C₂H₅ —H —H —OC₄H₉ —H —H 456 225—C₂H₅ —C₂H₅ —H —H —OC₂H₅ —H —H 428

Examples 226 to 237

According to the production process of Example 186, the followingcompounds of Examples 226 to 237 were produced (Table 21). Table 21 alsoshows physicochemical characteristics of these compounds. TABLE 21

Examples Ra Rb Rh MS(M + 1) 226 —C₂H₅ —C₂H₅ -2-FURYL 374 227 —C₂H₅ —C₂H₅-3-PYRIDYL 385 228 —C₂H₅ —C₂H₅ -4-PYRIDYL 385 229 —C₂H₅ —C₂H₅ -2-THIENYL390 230 —C₂H₅ —C₂H₅

388 231 —C₂H₅ —C₂H₅

399 232 —C₂H₅ —C₂H₅

404 233 —C₂H₅ —C₂H₅

386 234 —C₂H₅ —C₂H₅

415 235 —C₂H₅ —C₂H₅

440 236 —C₂H₅ —C₂H₅

420 237 —C₂H₅ —C₂H₅

446

Example 238 Production of2-{3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propyl}-3-methoxypyridinedihydrochloride

Hydrazine hydrate (0.18 ml, 3.6 mmol) and potassium hydroxide (136 mg,2.4 mmol) were added to a solution (5 ml) of3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(3-methoxypyridine-2-yl)-1-propanone(500 mg, 1.2 mmol) in diethylene glycol, and the resulting mixture washeated to 150° C. and stirred for 1 hour. After cooling to roomtemperature, water was added to the reaction mixture, followed byextraction with ethyl acetate. The organic layer was washed with asaturated salt solution, and dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified by silica gel column chromatography (eluent: ethylacetate/n-hexane=3/4). The solvent was distilled off under reducedpressure, and the residue was dissolved in 4 ml of ethanol. A 1Nhydrogen chloride ethanol solution (1.6 ml) was added, the solvent wasdistilled off under reduced pressure, and the residue was recrystallizedfrom an ethanol/ethyl acetate mixed solvent, to thereby obtain 320 mg(yield: 73%) of2-{3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propyl}-3-methoxypyridinedihydrochloride as a white powder.

Melting point: 169.4-171.2° C.

Example 239 Production of2-{3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionyl}benzonitrile

Zinc (II) cyanide (purity of 60%) (140 mg, 0.7 mmol) andtetrakis(triphenylphosphine)palladium (19 mg, 0.016 mmol) were added toa solution (1 ml) of1-(2-bromophenyl)-3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propane-1-one(150 mg, 0.33 mmol) in DMF, and the mixture was stirred with heating inan argon atmosphere at 100° C. for 2 hours. After cooling to roomtemperature, water and ethyl acetate was added to the reaction mixture,the resulting mixture was filtered through Celite, and the filtrate wasseparated into layers. The organic layer was washed with a saturatedsalt solution and dried over anhydrous magnesium sulfate. The solventwas distilled off under reduced pressure, and the residue was purifiedby silica gel column chromatography (eluent: ethylacetate/n-hexane=3/4). The solvent was distilled off under reducedpressure, and the residue was recrystallized from ethanol, to therebyobtain 70 mg (yield: 53%) of2-{3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionyl}benzonitrile ascolorless needles.

Melting point: 113.7-114.8° C.

Example 240 Production of methyl2-{3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionyl}benzoate

Sodium hydrogencarbonate (79 mg, 0.94 mmol) and methyl iodide (0.04 ml,0.56 mmol) were added to a solution (4 ml) of2-{3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionyl}benzoic acid (200mg, 0.47 mmol) in DMF, followed by stirring at room temperatureovernight. Water was added to the reaction mixture, and extraction withethyl acetate was performed. The organic layer was washed with asaturated salt solution, and dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified by silica gel column chromatography (eluent: ethylacetate/n-hexane=1/3). The solvent was distilled off under reducedpressure, and the residue was recrystallized from ethanol, to therebyobtain 190 mg (yield: 92%) of methyl2-{3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionyl}benzoate ascolorless needles.

Melting point: 91.7-92.9° C.

Example 241 Production of2-{3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionyl}-N,N-dimethylbenzamide

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC) (54 mg, 0.29 mmol),1-hydroxybenzotriazol (HOBT) (43 mg, 0.29 mmol), and a 50% aqueousdimethylamine solution (0.025 ml, 0.29 mmol) were added at roomtemperature to a solution (2 ml) of2-{3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionyl}benzoic acid (100mg, 0.24 mmol) in DMF, followed by stirring at the same temperature for2 hours. Water was added to the reaction mixture, and extraction withethyl acetate was performed. The organic layer was washed with asaturated aqueous sodium hydrogencarbonate solution, water and asaturated salt solution in this order, and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent: ethylacetate/n-hexane=1/3). The solvent was distilled off under reducedpressure, to thereby obtain 65 mg (yield: 61%) of2-{3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionyl}-N,N-dimethylbenzamideas a colorless oil.

NMRδppm(CDCl3); 7.88 (1H, d, J=7.4 Hz), 7.6-7.3 (4H, m), 7.3-7.2 (1H,m), 6.9-6.8 (2H, m), 4.2-4.1 (4H, m), 3.45 (2H, t, J=7.3 Hz), 3.20 (2H,t, J=7.2 Hz), 3.14 (3H, s), 2.76 (3H, s), 1.5-1.4 (6H, m)

Example 242 Production of3-[2-(3,4-dimethoxyphenyl)thiazole-4-yl]-1-(3,4-diacetoxyphenyl)propanone

Acetic anhydride (2 ml, 20 mmol) was added dropwise at room temperatureto a solution (4 ml) of3-[2-(3,4-dimethoxyphenyl)thiazole-4-yl]-1-(3,4-dihydroxyphenyl)propanone(320 mg, 0.78 mmol) in pyridine at room temperature, followed bystirring at the same temperature for 1 hour. Methanol (10 ml) was addedto the reaction mixture, stirring was carried out at room temperaturefor 1 hour, and the solvent was distilled off under reduced pressure.Subsequently, water was added, and extraction with ethyl acetate wasperformed. The residue was purified by silica gel column chromatography(eluent: ethyl acetate). The solvent was distilled off under reducedpressure, and the residue was recrystallized from an ethylacetate/n-hexane mixed solvent, to thereby obtain 195 mg (yield: 54%) of3-[2-(3,4-dimethoxyphenyl)thiazole-4-yl]-1-(3,4-diacetoxyphenyl)propanoneas colorless needles.

Melting point: 128-128.5° C.

Example 243 Production of3-[2-(3,4-dimethoxyphenyl)thiazole-4-yl]-1-(3,4-diethoxyphenyl)propanone

Ethyl iodide (0.48 ml, 6.0 mmol) and potassium carbonate (0.62 g, 4.5mmol) were added at room temperature to a solution (7 ml) of3-[2-(3,4-dimethoxyphenyl)thiazole-4-yl]-1-(3,4-dihydroxyphenyl)propanone(0.58 g, 1.5 mmol) in DMF, followed by stirring at 60° C. for 1 hour.After cooling to room temperature, ethyl acetate was added to thereaction mixture, the resulting mixture was filtered, and the solventwas distilled off under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2).The solvent was distilled off under reduced pressure, and the residuewas recrystallized from an ethyl acetate/n-hexane mixed solvent, tothereby obtain 290 mg (yield: 44%) of3-[2-(3,4-dimethoxyphenyl)thiazole-4-yl]-1-(3,4-diethoxyphenyl)propanoneas a white powder.

Melting point: 141.3-142.4° C.

Examples 244 to 247

According to the production process of Example 186, the followingcompounds of Examples 244 to 247 were produced (Table 22). TABLE 22 Ex.Compound MS (M + 1) 244 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]- 4341-naphthalene-1-yl-1-propanol 2453-[2-(3,4-diethoxyphenyl)thiazole-4-yl]- 4341-naphthalene-2-yl-1-propanol 2463-[2-(3,4-diethoxyphenyl)thiazole-4-yl]- 4361-quinoxaline-6-yl-1-propanol 247 1-benzo[1,3]dioxol-5-yl-3-[2-(3,4- 428diethoxyphenyl)thiazol-4-yl]-1-propanol

Example 248

According to the production process of Example 58, the followingcompound was produced.

-   Methyl    2-[2-(3,4-diethoxyphenyl)thiazole-4-ylmethyl]-2-(3-ethoxypyridine-2-yl)-3-oxobutyrate

NMRδppm(CDCl3); 8.22 (1H, dd, J=1.4 Hz, 4.3 Hz), 7.5-7.3 (4H, m),6.9-6.8 (2H, m), 4.8-4.6 (1H, m), 4.2-4.0 (4H, m), 3.90 (3H, s), 3.65(3H, s), 3.0-2.8 (2H, m), 2.6-2.3 (2H, m), 1.5-1.4 (6H, m)

Example 249

According to the production process of Example 87, the followingcompound was produced.

-   3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(3-ethoxypyridine-2-yl)-1-butanone

NMRδppm(CDCl3); 8.30-8.20 (1H, m), 7.51 (1H, d, J=1.8 Hz), 7.5-7.3 (3H,m), 6.9-6.8 (2H, m), 4.3-4.1 (4H, m), 3.89 (3H, s), 3.20 (2H, t, J=7.3Hz), 2.91 (2H, t, J=7.5 Hz), 2.2-2.1 (2H, m), 1.5-1.4 (6H, m)

Example 250

According to the production process of Example 90, the followingcompound was produced.

-   2-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(2-methoxyphenyl)-ethanone

NMRδppm(CDCl3); 7.79 (1H, dd, 1.8, 7.7 Hz), 7.49 (1H, d, J=2.1 Hz),7.49-7.46 (1H, m), 7.42 (1H, dd, J=2.1, 8.4 Hz), 7.06 (1H, s), 7.03-7.00(1H, m), 6.98 (1H, d, J=8.4 Hz), 6.88 (1H, d, J=8.4 Hz), 4.55 (2H, s),4.18 (2H, q, J=7.0 Hz), 4.14 (2H, q, J=7.0 Hz), 3.92 (3H, s), 1.48 (3H,t, J=7.0 Hz), 1.47 (3H, t, J=7.0 Hz)

Test Example 1 Confirmatory Test for Phosphodiesterase (PDE) 4Inhibitory Activity

Using the compounds of Examples 1, 78, 87, 88, 99, 100, 106, 107, 158,162, 165, 167, 174, 175, 187, 227, 238 and 239 as test substances, thefollowing test was conducted to evaluate their phosphodiesterase (PDE) 4inhibitory activity.

(1) Mass Preparation of Plasmids

Plasmids containing genes coding for human PDE4D (HPDE4D) (stored inOtsuka America Pharmaceutical, Inc., Maryland Research Laboratories)were transformed into Escherichia coli, and mass cultured. The plasmidswere then purified using EndoFree™ Plasmid Mxi Kit (Qiagen).

(2) Mass Expression and Purification of PDE4D

African green monkey kidney-derived COS-7 cells (RCB 0539) weresubcultured in a DMEM medium containing 100 units/ml penicillin, 100μm/ml streptomycin and 10% FBS. The plasmids prepared in (1) weretransfected into the cells, using LipofectAMINE™ 2000 Reagent(hereinafter referred to as “LF2000”, a product of Invitroge), accordingto the attached protocol. For comparison, pcDNA3.1 was transfected as acontrol vector. The COS-7 cells were inoculated into 10 cm diameterpetri dishes on the day before transfection, so that the cells reached90% confluence on the day of transfection. Twelve micrograms of theplasmids diluted with 0.9 ml of OPTI-MEM I (Invitrogen) (a plasmidsolution; Solution A) and 30 μl of LF2000 diluted with 0.9 ml ofOPTI-MEM I (a LF2000 solution; Solution B) were prepared per petri dish,and allowed to stand at room temperature for 5 minutes. Solutions A andB were then mixed together and allowed to stand at room temperature for20 minutes. The mixture was added to the cultured cells, and incubationwas performed overnight at 37° C. in an atmosphere of 5% CO₂. Theculture medium was changed on the following day, incubation wascontinued overnight, and the cells were collected by the followingprocedure. First, the cells were washed once with PBS (Sigma), and 2 mlof Trypsin-EDTA solution (Sigma) was added per petri dish, spread overthe dish and removed. The cells were then allowed to stand at 37° C. for2 to 3 minutes, separated from the petri dish and suspended in a medium.The suspension was placed in a centrifuge tube, and centrifuged at 200×gand 4° C. for 5 minutes. The supernatant was then removed. The cellswere further washed with PBS and stored at −80° C. A KHEM buffer (50 mMHepes, 50 mM KCl, 10 mM EGTA, 1.92 mM MgCl₂, pH 7.2) containing 1 mMDTT, 40 μg/ml PMST, 156 μg/ml benzamidine, 1 μg/ml apotinin, 1 μg/mlleupeptin, 1 μg/ml pepstatin A, and 1 μg/ml antipain was added to thecells that had been stored, and the resulting mixture was placed in aglass homogenizer and homogenized on ice. The cell suspension wascentrifuged at 100×g and 4° C. for 5 minutes, and the supernatant wasfurther centrifuged at 100,000×g for 1 hour. Thereafter, the supernatantwas dispensed into new tubes as a PDE4D enzyme solution, and stored inan ultra-low-temperature freezer. The protein concentration of the PDE4Denzyme solution was then measured.

(3) Determination of Dilution Factor of PDE4D Enzyme Solution

The PDE4D enzyme solution prepared in (2) was diluted 10-, 25-, 50-,100-, 200-, 400- and 800-fold with 20 mM Tris-HCl (pH 7.4), and thePDE4D activities of the diluted enzyme solutions were measured by themethod described in (4) to determine the optimum dilution factor toobtain a PDE4D enzyme solution in which degraded cAMP constituted 10 to30% of the total cAMP.

(4) Measurement of PDE4D Inhibitory Activity

The necessary amount of each test substance was weighed out anddissolved in 100% DMSO to a concentration of 10 mM. The resultingsolutions were stored in a freezer as test substance stock solutions.Before the inhibitory activity measurement, the stock solutions weremelted, diluted 2-fold with 100% DMSO to a concentration of 5 mM, andfurther diluted with 100% DMSO to obtain test substance solutions with10 graded concentrations. Each test substance solution was added to a1.2 ml tube containing 23 μl of 20 mM Tris-HCl (pH 7.4). Twenty fivemicroliters of the PDE4D enzyme solution at the optimum dilution factordetermined in (3) was added under ice cooling, and 50 μl of a substratesolution, which contained 2 μM [³H]cAMP obtained by dilution with 20 mMTris-HCl (pH 7.4) containing 10 mM MgCl₂, was added. The final DMSOconcentration in the reaction mixture was 2%. After stirring, themixture was incubated at 30° C. for 10 minutes. After completion of theincubation, the tubes were placed in a boiling water bath for 3 minutesto terminate the reaction. The tubes were cooled in ice, and 25 μl of0.2 μg/ml snake venom solution was added. After stirring, incubation wascarried out at 30° C. for 10 minutes. After completion of incubation,0.4 ml of a Dowex 1×8 resin solution prepared using a EtOH:H₂O (1:1)mixture was added. After stirring, the mixture was allowed to stand atroom temperature for at least 1 hour. Fifty microliters of each of thesupernatants in the tubes was placed in a well of a Topcount plate, andthe plate was dried overnight. The radioactivity (cpm) of [³H] wasmeasured using a Topcount. Specifying the radioactivity of [³H] as Xcpm, the radioactivity of the total [³H]cAMP added in the reactionsystem as T cpm, and the protein concentration of the reaction mixtureas Y mg/ml, the PDE4D activity in the reaction mixture was found fromthe following equation.$\underset{({{pmol}\text{/}{mim}\text{/}{mg}})}{{PDE}\quad 4\quad D\quad{activity}} = {\frac{391.67}{50} \times \frac{X}{T} \times \frac{10^{- 11}}{10} \times 10^{12} \times \frac{1}{0.1} \times \frac{1}{Y}}$

To find the PDE4D inhibitory activities of the test substances, cpm inthe absence of the test substances, from which cpm in the absence of theenzyme had been subtracted, was set as 100%, and the rates of inhibitionby the test substances were expressed as percentages of control.Thereafter, the IC₅₀ value (the concentration that inhibits the PDE4activity by 50%) of each test substance was calculated.

Table 23 shows the results. The results demonstrate that the compoundsrepresented by Formula (1) have excellent PDE4 inhibitory activity.TABLE 23 Test substance IC₅₀ value (μM) Compound of Example 1 0.0236Compound of Example 78 0.0100 Compound of Example 87 0.0002 Compound ofExample 88 0.0004 Compound of Example 99 0.0290 Compound of Example 1000.0023 Compound of Example 106 0.0057 Compound of Example 107 0.0058Compound of Example 158 0.0057 Compound of Example 162 0.0016 Compoundof Example 165 0.0150 Compound of Example 167 0.0100 Compound of Example174 0.0100 Compound of Example 175 0.0330 Compound of Example 187 0.0066Compound of Example 227 0.0290 Compound of Example 238 0.0072 Compoundof Example 239 0.0097

Test Example 2 Measurement of TNF-α Production Inhibitory Activity

The following tests were performed to evaluate TNF-α productioninhibitory activity.

(1) Separation of Human Peripheral Blood Mononuclear Cells

A peripheral blood sample was obtained from a healthy adult donor whohad signed a written informed consent. Thirty milliliters of the bloodsample, which had been heparinized, was dispensed into a Leucosep tube(Greiner) containing 16 ml of a lymphocyte separation solution (NakaraiChemical, Ltd.) under the filter barrier, and centrifuged at 1000×g for15 minutes.

The intermediate layer corresponding to a mononuclear cell fraction wascollected in a 50 ml centrifuge tube, and washed twice with a RPMI 1640medium. After trypan blue staining, the viable count was determined andadjusted to 2×10⁶ cells/ml with RPMI 1640 medium.

(2) Induction of TNF-α Production

E. coli (Serotype 055:B5)-derived LPS, which had been dissolved in aRPMI 1640 medium to a concentration of 5 mg/ml, sterilized by filtrationand stored in a freezer, was melted and diluted with a RPMI 1640 mediumto 10 μg/ml. The test substances were dissolved in DMSO to obtainsolutions with a concentration of 50 times the final use concentration.One microliter of each of the graded concentration test substancesolutions, 149 μl of RPMI 1640 medium, 50 μl of LPS solution (finalconcentration: 1 μg/ml), 50 μl of fetal bovine serum, and 50 ml of theperipheral blood mononuclear cell suspension were dispensed to each wellof a 48-well plate and incubated at 37° C. for 24 hours.

(3) Measurement of TNF-α Concentration

After completion of the incubation, the culture supernatant wascollected from each well, and the TNF-α concentration in the supernatantwas measured by ELISA method (Human TNF-α Eli-pair, Diaclone). The TNF-αconcentration caused by LPS stimulation in the absence of testsubstances was set as 100%, and the rates of inhibition by the testsubstances were expressed as percentages of the control, and the IC₅₀value (the concentration that inhibits TNF-α production by 50%) of eachtest substance was calculated.

Table 24 shows the results. The results demonstrate that the compoundsrepresented by Formula (1) have IFN-α production inhibitory activity.TABLE 24 Test Substance IC₅₀ value (μM) Compound of Ex. 1 0.008 Compoundof Ex. 48 0.25 Compound of Ex. 51 0.8 Compound of Ex. 52 0.13 Compoundof Ex. 56 0.16 Compound of Ex. 89 0.007 Compound of Ex. 91 0.543Compound of Ex. 153 0.183

Test Example 3 Measurement of IL-4 Production Inhibitory Activity

The following tests were performed to evaluate IL-4 productioninhibitory activity.

(1) Separation of Mouse Spleen Cells

The abdomens of six- to ten-week-old male BALB/c mice were incised underether anesthesia, and the spleens were excised. The spleens wereseparated into pieces by forcing them through a mesh using a glasspestle, and the spleen cells were suspended in RPMI 1640 medium. Thesuspension was filtered through a Cell Strainer and centrifuged at 100×gfor 10 minutes. The cell pellets were suspended in a red blood cellsolution (0.75% ammonium chloride, 17 mM tris-hydrochloric acid buffer)and centrifuged. Thereafter, a RPMI 1640 medium was added to the cellpellets to resuspend the cells. After centrifugation, the cells werewashed twice, and the viable count was determined by trypan bluestaining and adjusted to 2×10⁶ cells/ml with RPMI 1640 medium.

(2) Induction of IL-4 Production

ConA, which had been dissolved in a cell culture solution (a RPMI 1640medium containing 10% fetal bovine serum) to a concentration of 5 mg/ml,sterilized by filtration and stored in a freezer, was melted and dilutedwith a cell culture solution to 50 μg/ml. The test substances weredissolved in DMSO, diluted with a cell culture solution to aconcentration of 10 times the final use concentration. Fifty microlitersof each of the graded concentration test substance solutions, 150 μl ofcell culture solution, 50 μl of ConA solution (final concentration: 5μl/ml) and 20 μl of mouse spleen cell suspension were dispensed to eachwell of a 48-well plate and incubated at 37° C. for 48 hours.

(3) Measurement of IL-4 Concentration

After completion of the incubation, the culture supernatant wascollected from each well, and the IL-4 concentration of the supernatantwas measured by the ELISA method (mouse IL-4 EIA kit, BD Pharmingen).The IL-4 concentration caused by ConA stimulation in the absence of testsubstances was set as 100%, the rates of inhibition by the testsubstances were expressed as percentages of the control, and the IC₅₀value of each test substance was calculated as the test substanceconcentration that inhibits IL-4 production by 50%.

Formulation Example 1 Ointment

One gram of the compound of the present invention was dispersed in 10 gof liquid paraffin to obtain a dispersion. A base was prepared byheating and mixing 3 g of paraffin, 5 g of white beeswax and 81 g ofwhite petrolatum, and cooled, and when it had cooled to about 60° C.,the above dispersion was added. After mixing, the mixture was cooled toobtain an ointment.

Formulation Example 2 Cream

One gram of the compound of the present invention was dispersed in anaqueous solution containing 10 g of purified water and 1 g ofpolyoxyethylene hydrogenated castor oil 60, to obtain a dispersion. Anemulsion base, comprising 25 g of white petrolatum, 20 g of stearylalcohol, 12 g of propylene glycol, 3 g of polyoxyethylene hydrogenatedcastor oil 60, 1 g of glyceryl monostearate, 0.1 g of methylparaoxybenzoate, 0.1 g of propyl paraoxybenzoate and 26.8 g of purifiedwater, was prepared with heating. The obtained emulsion base was cooled,and when it had cooled to 60° C., the above dispersion was added. Aftermixing, the mixture was cooled to obtain a cream.

INDUSTRIAL APPLICABILITY

The compound of the present invention exhibits specific inhibitoryactivity against PDE4, and thus is useful as an active ingredient of aPDE4 inhibitor.

Further, the compound of the present invention, based on its specificinhibitory activity against PDE4, is useful as a preventive ortherapeutic agent for atopic dermatitis and various other diseases.

1. A compound represented by Formula (1), an optical isomer thereof, ora salt thereof:

wherein R1 is a di-C₁₋₆ alkoxyphenyl group; R2 is any one of thefollowing groups (a) to (t): (a) a phenyl group in which the phenyl ringmay be substituted with one or more members selected from the groupconsisting of (a-1) hydroxy groups, (a-2) halogen atoms, (a-3)unsubstituted or halogen-substituted C₁₋₆ alkyl groups, (a-4)unsubstituted or halogen-substituted C₁₋₆ alkoxy groups, (a-5) C₁₋₆alkoxy-C₁₋₆ alkoxy groups, (a-6) amino-C₁₋₆ alkoxy groups which may besubstituted with a C₁₋₆ alkyl group or groups, (a-7) methylenedioxygroups, (a-8) carboxyl groups, (a-9) phenoxy groups, (a-10) C₁₋₆alkoxycarbonyl groups, (a-11) C₁₋₆ alkanoyloxy groups, (a-12) C₁₋₆alkanoyl groups, (a-13) cyano groups, (a-14) nitro groups, (a-15) C₁₋₆alkylcarbamoyl groups, (a-16) aminosulfonyl groups, (a-17) amino groupswhich may be substituted with a C₁₋₆ alkyl group or groups, (a-18) C₁₋₆alkanoylamino groups, (a-19) C₁₋₆ alkylthio groups, (a-20) phenylgroups, (a-21) pyrazolyl groups, (a-22) imidazolyl groups, (a-23)triazolyl groups, (a-24) morpholino groups, (a-25) pyrrolidinyl groups,(a-26) piperazinylcarbonyl groups which may be substituted with a C₁₋₆alkyl group or groups, and (a-27) phenyl-C₁₋₆ alkoxy groups; (b) anaphthyl group; (c) a pyridyl group in which the pyridine ring may besubstituted with one or more members selected from the group consistingof (c-1) hydroxy groups, (c-2) C₁₋₆ alkyl groups, (c-3) C₁₋₆ alkoxygroups, (c-4) phenyl-C₁₋₆ alkoxy groups, and (c-5) C₁₋₆ alkoxycarbonylgroups; (d) a furyl group in which the furan ring may be substitutedwith a C₁₋₆ alkyl group or groups; (e) a thienyl group in which thethiophene ring may be substituted with one or more members selected fromthe group consisting of (e-1) halogen atoms, (e-2) C₁₋₆ alkyl groups,and (e-3) C₁₋₆ alkoxy groups; (f) an isoxazolyl group in which theisoxazolyl ring may be substituted with a C₁₋₆ alkyl group or groups;(g) a thiazolyl group in which the thiazole ring may be substituted withone or more members selected from the group consisting of (g-1) C₁₋₆alkyl groups, and (g-2) phenyl groups which may be substituted with aC₁₋₆ alkoxy group or groups; (h) a pyrrolyl group in which the pyrrolering may be substituted with a C₁₋₆ alkyl group or groups; (i) animidazolyl group in which the imidazole ring may be substituted with aC₁₋₆ alkyl group or groups; (j) a tetrazolyl group; (k) a pyrazinylgroup; (l) a thienothienyl group; (m) a benzothienyl group; (n) anindolyl group in which the indole ring may be substituted with a C₁₋₆alkoxy groups or groups; (o) a benzimidazolyl group in which thebenzimidazole ring may be substituted with a C₁₋₆ alkyl group or groups;(p) an indazolyl group; (q) a quinolyl group; (r) a1,2,3,4-tetrahydroquinolyl group in which the1,2,3,4-tetrahydroquinoline ring may be substituted with an oxo group orgroups; (s) a quinoxalinyl group; and (t) a 1,3-benzodioxolyl group; andA is any one of the following groups (i) to (vi): (i) —CO—B— wherein Bis a C₁₋₆ alkylene group; (ii) —CO—Ba— wherein Ba is a C₂₋₆ alkenylenegroup; (iii) —CH(OH)—B— wherein B is as defined above; (iv)—COCH(COOR3)-Bb- wherein R3 is a C₁₋₆ alkyl group and Bb is a C₁₋₆alkylene group; and (v) -Bc- wherein Bc is a C₂₋₆ alkylene group.
 2. Acompound according to claim 1, wherein, in Formula (1), R1 is a3,4-di-C₁₋₆ alkoxyphenyl group; an optical isomer thereof; or a saltthereof
 3. A compound according to claim 1, wherein, in Formula (1), R2is (a) a phenyl group in which the phenyl ring may be substituted withone or more members selected from the group consisting of (a-1) hydroxygroups, (a-2) halogen atoms, (a-3) unsubstituted or halogen-substitutedC₁₋₆ alkyl groups, (a-4) unsubstituted or halogen-substituted C₁₋₆alkoxy groups, (a-5) C₁₋₆ alkoxy-C₁₋₆ alkoxy groups, (a-6) amino-C₁₋₆alkoxy groups which may be substituted with a C₁₋₆ alkyl group orgroups, (a-7) methylenedioxy groups, (a-8) carboxyl groups, (a-9)phenoxy groups, (a-10) C₁₋₆ alkoxycarbonyl groups, (a-11) C₁₋₆alkanoyloxy groups, (a-12) C₁₋₆ alkanoyl groups, (a-13) cyano groups,(a-14) nitro groups, (a-15) C₁₋₆ alkylcarbamoyl groups, (a-16)aminosulfonyl groups, (a-17) amino groups which may be substituted witha C₁₋₆ alkyl group or groups, (a-18) C₁₋₆ alkanoylamino groups, (a-19)C₁₋₆ alkylthio groups, (a-20) phenyl groups, (a-21) pyrazolyl groups,(a-22) imidazolyl groups, (a-23) triazolyl groups, (a-24) morpholinogroups, (a-25) pyrrolidinyl groups, (a-26) piperazinylcarbonyl groupswhich may be substituted with a C₁₋₆ alkyl group or groups, and (a-27)phenyl-C₁₋₆ alkoxy groups; (c) a pyridyl group in which the pyridinering may be substituted with one or more members selected from the groupconsisting of (c-1) hydroxy groups, (c-2) C₁₋₆ alkyl groups, (c-3) C₁₋₆alkoxy groups, (c-4) phenyl-C₁₋₆ alkoxy groups, and (c-5) C₁₋₆alkoxycarbonyl groups; (d) a furyl group in which the furan ring may besubstituted with a C₁₋₆ alkyl group or groups; (e) a thienyl group inwhich the thiophene ring may be substituted with one or more membersselected from the group consisting of (e-1) halogen atoms, (e-2) C₁₋₆alkyl groups, and (e-3) C₁₋₆ alkoxy groups; (g) a thiazolyl group inwhich the thiazole ring may be substituted with one or more membersselected from the group consisting of (g-1) C₁₋₆ alkyl groups, and (g-2)phenyl groups which may be substituted with a C₁₋₆ alkoxy group orgroups; (h) a pyrrolyl group in which the pyrrole ring may besubstituted with a C₁₋₆ alkyl group or groups; or (i) an imidazolylgroup in which the imidazole ring may be substituted with a C₁₋₆ alkylgroup or groups; an optical isomer thereof; or a salt thereof.
 4. Acompound according to claim 1, wherein, in Formula (1), A is (i) —CO—B—wherein B is an ethylene group, a methylene group or a trimethylenegroup; (ii) —CO—Ba— wherein Ba is a vinylidene group; (iii) —CH(OH)—B—wherein B is a methylene group or an ethylene group; (iv)—COCH(COOR3)-Bb- wherein R3 is a methyl group, an ethyl group or atert-butyl group and Bb is a methylene group or an ethylene group; or(v) -Bc- wherein Bc is an ethylene group, a trimethylene group or atetramethylene group; an optical isomer thereof; or a salt thereof.
 5. Acompound according to claim 1, wherein, in Formula (1), R1 is a3,4-di-C₁₋₆ alkoxyphenyl group; R2 is (a) a phenyl group in which thephenyl ring may be substituted with one or more members selected fromthe group consisting of (a-1) hydroxy groups, (a-2) halogen atoms, (a-3)unsubstituted or halogen-substituted C₁₋₆ alkyl groups, (a-4)unsubstituted or halogen-substituted C₁₋₆ alkoxy groups, (a-5) C₁₋₆alkoxy-C₁₋₆ alkoxy groups, (a-6) amino-C₁₋₆ alkoxy groups which may besubstituted with a C₁₋₆ alkyl group or groups, (a-7) methylenedioxygroups, (a-8) carboxyl groups, (a-9) phenoxy groups, (a-10) C₁₋₆alkoxycarbonyl groups, (a-11) C₁₋₆ alkanoyloxy groups, (a-12) C₁₋₆alkanoyl groups, (a-13) cyano groups, (a-14) nitro groups, (a-15) C₁₋₆alkylcarbamoyl groups, (a-16) aminosulfonyl groups, (a-17) amino groupswhich may be substituted with a C₁₋₆ alkyl group or groups, (a-18) C₁₋₆alkanoylamino groups, (a-19) C₁₋₆ alkylthio groups, (a-20) phenylgroups, (a-21) pyrazolyl groups, (a-22) imidazolyl groups, (a-23)triazolyl groups, (a-24) morpholino groups, (a-25) pyrrolidinyl groups,(a-26) piperazinylcarbonyl groups which may be substituted with a C₁₋₆alkyl group or groups, and (a-27) phenyl-C₁₋₆ alkoxy groups; (c) apyridyl group in which the pyridine ring may be substituted with one ormore members selected from the group consisting of (c-1) hydroxy groups,(c-2) C₁₋₆ alkyl groups, (c-3) C₁₋₆ alkoxy groups, (c-4) phenyl-C₁₋₆alkoxy groups, and (c-5) C₁₋₆ alkoxycarbonyl groups; (d) a furyl groupin which the furan ring may be substituted with a C₁₋₆ alkyl group orgroups; (e) a thienyl group in which the thiophene ring may besubstituted with one or more members selected from the group consistingof (e-1) halogen atoms, (e-2) C₁₋₆ alkyl groups, and (e-3) C₁₋₆ alkoxygroups; (g) a thiazolyl group in which the thiazole ring may besubstituted with one or more members selected from the group consistingof (g-1) C₁₋₆ alkyl groups, and (g-2) phenyl groups which may besubstituted with a C₁₋₆ alkoxy group or groups; (h) a pyrrolyl group inwhich the pyrrole ring may be substituted with a C₁₋₆ alkyl group orgroups; (i) an imidazolyl group in which the imidazole ring may besubstituted with a C₁₋₆ alkyl group or groups; and A is (i) —CO—B—wherein B is as defined above; (ii) —CO—Ba wherein Ba is as definedabove; (iii) —CH(OH)—B— wherein B is as defined above; (iv)—COCH(COOR3)-Bb- wherein R3 and Bb are as defined above; or (v) -Bc-wherein Bc is as defined above; an optical isomer thereof; or a saltthereof.
 6. A pharmaceutical composition comprising a compound accordingto claim 1, an optical isomer thereof, or a salt thereof.
 7. Aphosphodiesterase 4 inhibitor comprising as an active ingredient acompound according to claim 1, an optical isomer thereof, or a saltthereof.
 8. A preventive or therapeutic agent for atopic dermatitis,comprising as an active ingredient a compound according to claim 1, anoptical isomer thereof, or a salt thereof.
 9. A method for treatingatopic dermatitis, comprising the step of administering to a human ornon-human mammal an effective amount of a compound according to claim 1,an optical isomer thereof, or a salt thereof.
 10. Use of a compoundaccording to claim 1, an optical isomer thereof, or a salt thereof, forproducing a preventive or therapeutic agent for atopic dermatitis. 11.Use of a compound according to claim 1, an optical isomer thereof, or asalt thereof, for producing a phosphodiesterase 4 inhibitor.